端粒相关蛋白TRF1和PinX1的翻译后修饰研究及功能解析
|
摘要
端粒是一种特殊的由富含G的重复DNA序列和相关蛋白质组成的复合体,位于真核细胞染色体末端,起到保护末端染色体不被降解以及防止染色体末端融合的重要作用。端粒功能的缺失将导致细胞基因组的不稳定,从而大大增加正常细胞转化为癌细胞的风险。在大多数肿瘤细胞中,端粒长度主要由一种特殊的RNA逆转录酶即端粒酶以及端粒相关蛋白来调节,端粒相关蛋白通过直接或间接与端粒DNA相互作用来维持端粒结构和功能的稳定。近年来,越来越多的证据表明：传统的端粒蛋白不仅仅在端粒末端起到保护端粒结构的作用,他们还直接参与了细胞有丝分裂进程的复杂调控,例如端粒相关蛋白TRF1,TRF1的蛋白表达量在整个细胞周期中呈现动态变化,此外,TRF1能够和微管,微管相关蛋白EB1以及一些重要的纺锤体检验点蛋白比如Mad1,Nek2以及Plk1等有相互作用,这些结果表明：TRF1及其相互作用蛋白可能在细胞周期的调控中起到重要作用。
由于DNA末端复制问题的存在(即细胞每分裂一次端粒就丢失数十至数百个不等的碱基),大部分肿瘤细胞和永生化细胞株例如睾丸细胞,均通过端粒酶维持端粒长度的稳定,但有一小部分肿瘤细胞,是依靠端粒延伸替代机制的激活来维持自身端粒长度的稳定,而在ALT机制维持端粒长度的调节过程中,ALT相关PML小体起到至关重要的作用。研究表明,ALT机制的核心是端粒染色体的互换重组,这个互换重组的过程在APB发生且受到精确调控,之前有研究表明TRF1的SUMO化影响了APB的形成。我们课题组此前的研究亦表明,TRF1受PML3招募上PML小体,且PML3在维持APB的形成中起到关键作用,但关于TRF1定位于APB的具体调控机制还不清楚。
泛素-蛋白酶体途径是真核生物体内重要的蛋白降解途径之一。针对目标蛋白的泛素化降解是一个多步骤过程,Ub首先由E1激活酶激活,进而被转移到E2接合酶的活化胱氨酸上,再由一个特异的E3泛素连接酶将Ub从接合酶转移到靶蛋白上。其中,含有HECT结构域的E3连接酶能够和泛素形成硫酯中间体,进而直接催化靶蛋白的泛素化。而含有锌指环结构的E3连接酶则作为支架蛋白将E2接合酶与底物招募到一起,将Ub直接转移到底物上,其本身并不直接参与靶蛋白的泛素化。SCFβ-TrCP即是一种含有锌指结构的E3连接酶复合体,由四种核心亚基组成：Skp1、Cull,β-TrCP和Rbxl。其中Rbxl负责募集E2接合酶并催化亚基,Cull作为分子支架在其氨基端与Skpl结合,在羧基端和Rbxl以及E2接合酶相互作用。Rbx1和其他亚基之间的支架参与底物的选择,β-TrCP通过其F-box结构域与Skpl相互结合,并通过其WD40重复性序列特异性识别底物,多数情况下β-TrCP能够识别底物上的一个特殊的磷酸化氨基酸序列,但亦有报道称β-TrCP也能够识别非磷酸化蛋白。
本课题组通过体内免疫沉淀结合蛋白质质谱鉴定的方法,从稳定表达Flag-TRF1的Hela细胞中分离出了8个可能的TRF1相互作用蛋白,序列比对发现,β-TrCP有可能是一个新的TRFl结合蛋白质,我们通过一系列体内实验证实了β-TrCP能够与TRF1在体内相互作用,外源性过量表达β-TrCP能够导致TRF1的表达量降低,进一步研究显示,β-TrCP通过促进TRF1的泛素化降解调控TRF1的蛋白表达水平,并且这一调控功能依赖于β-TrCP的F-box结构域。令人意外的是,我们发现在端粒酶阴性细胞中,PML3可以保护TRF1不受β-TrCP的降解,过量表达β-TrCP能够调控APB的形成,而利用siRNA抑制内源性β-TrCP的表达,则使得APB数量明显减少,提示β-TrCP在调控APB的形成中起到重要作用。本次研究首次发现了TRF1是一个新的β-TrCP底物蛋白,并且证明了β-TrCP在APB形成的调控中起到重要作用,为进一步探讨APB的形成及调控机制提供了新的佐证及线索。
PinX1最初是作为一个新的TRF1相互作用蛋白,由Lu等在2001年首次报道,PinX1含有两个特殊的结构域：通常存在于RNA结合蛋白中的G-patch结构域以及端粒酶抑制结构域(TID)。PinX1是迄今为止发现的最强力的端粒酶抑制因子,PinX1的端粒酶抑制作用通过其本身与hTERT和hTR直接作用来实现,尽管如此,PinX1在酵母中的同源物Gnolp是否具有端粒酶抑制作用目前还存在争议。除了端粒定位以及端粒酶抑制作用外,PinX1还被发现在端粒酶阳性细胞株中能够定位于核仁,并且能够增强TRF1在核仁的聚集,表明PinX1还具有其他功能。我们课题组在前期的研究中,意外的发现在有丝分裂期,PinX1能够定位于染色体周边以及动点外层,在有丝分裂期,SiRNA敲除PinX1够导致滞后染色体的出现,在间期,敲除PinX1能够导致小核细胞的增多,但关于PinX1具体的调控机制仍不清楚。
在前期工作的基础上,本课题组利用酵母双杂交的方法来寻找新的PinX1的相互作用蛋白,我们成功的从人睾丸cDNA文库中筛选到了19个阳性克隆,通过序列比对,我们发现Plk1可能是一个新的PinX1的相互作用蛋白。通过体内体外实验,进一步证实了PinX1与Plk1之间的相互作用。免疫荧光实验显示：PinXl与Plk1在有丝分裂期共定位于纺锤体上。PinX1通过其92-254段与Plk1的激酶结构域直接结合。此外,我们通过体外磷酸化的方法鉴定出PinX1是一个新的Plk1的磷酸化底物蛋白。通过蛋白质磷酸化质谱技术,我们得到了潜在的PinX1的磷酸化位点,我们构建了PinX1的非磷酸化突变体和模拟磷酸化突变体,并在体外磷酸化实验中得到了验证。进一步的研究表明,PinX1在体内能发生泛素化修饰,Plk1对PinX1的磷酸化调控PinX1的蛋白表达量变化。通过流式细胞术和免疫荧光的方法,我们发现外源转染PinX1的非磷酸化突变体可导致细胞阻滞到有丝分裂期,并且导致错误染色体的排列。综上,本部分研究证实了PinX1是一个新的Plk1的底物蛋白,Plk1通过磷酸化PinX1促进PinX1的泛素化降解,更进一步,我们发现了PinX1的磷酸化对于细胞的有丝分裂正常进行是必须的。通过以上研究,我们阐明了PinX1的磷酸化修饰的具体机制和功能,为深入阐明细胞有丝分裂过程的调控机制提供了新的实验证据和思路。
综上所述,本项研究分为二个部分,第一部分,我们首次发现了β-TrCP与TRF1之间的相互作用,β-TrCP是一个新的负责TRF1泛素化降解的泛素-蛋白质连接酶,在端粒酶阴性细胞株中,PML3能够特异性的保护TRF1不受β-TrCP的降解,且β-TrCP在调控APB的形成中起重要作用。为深入探讨APB的形成及调控机制提供了新的佐证和线索。本课题的第二部分研究,首次发现了PinX1与Plk1的相互作用,PinX1是Plkl的磷酸化底物蛋白,Plk1通过磷酸化PinX1促进PinX1的泛素化降解,并且PinX1的磷酸化对于细胞有丝分裂的正常进行是必须的,这为深入研究细胞有丝分裂的调控机制提供了新的实验证据和思路。
Telomere is a specialized nucleoprotein complex which contains repetitive G-rich DNA sequences and partner proteins to protect the chromosomal ends from degradation and to prevent the chromosomal end-to-end fusion. Dysfunction of telomere leads to genome instability and higher incidence of cancer in the aged cells. Although the maintenance of telomere length is mainly performed by a specific reverse transcriptase named telomerase in most malignant cancer cells, telomere-associated proteins are essential for adequate maintenance of telomeric DNA. Telomere-associated proteins directly and indirectly interact with telomeric DNA and contribute to telomere structure and function. Moreover, mounting evidence suggests that telomeric associated proteins may play important roles in cell cycle progression. For examble, expression level of TRF1 is regulated during the cell cycle, besides, it is reported that TRF1 can interact with microtubule, EB1 and some spindle checkpoint proteins such as Madl and Nek2. These results indicate that TRF1 and its partner telomeric interacting proteins may function as important signals in cell cycle.
The ubiquitin-proteasome system, the most important protein degradation pathway in eukaryotic cells, regulates a host of critical cellular functions such as cell cycle progression and apoptosis through mediating the selective and time-dependent degradation of short-lived regulatory proteins. Previous studies reported that TRF1 can be ubiquitiated by some E3 ligases such as FBX4 and RLIM, indicating the importance of ubiquitin-proteasome system in regulating telomeric associated proteins.
Telomeres can be shorten by 50-150 base pairs (bp) per cell division owing to the end-replication problem of the chromosome, which leads to replicative senescence when the telomere length reaches a critical point in normal somatic cells. Most cancer cells elongate there telomeres by activating telomerase. However, there are some cancer cells cannot activate telomerase and use telomere homologous recombination to elongate telomeres, a mechanism termed alternative lengthening of telomeres (ALT). The presence of ALT-associated PML bodies (APBs) is a hallmark of ALT cells. It has been suggested that APBs may have an integral role in the ALT mechanism, but the precise mechanism of APBs formation remains to be elucidated. Previous studies revealed that TRFl and its sumoylation is essential for the formation of APBs. Our recent study also showed that PML3 can assist the recruitment of TRF1 to APBs and is essential for APBs formation, but the detailed mechanism of the APBs formation is unknown.
The ubiquitin-proteasome system is one of the most important protein degradation pathway in eukaryotic cells. Ubiquitination of target proteins is a multistep process. After activation by E1 enzyme, ubiqui tin is transferred to an active cystine of a ubiquitin-conjugating enzyme (E2). A ubiquitin ligase (E3) then transfers ubiquitin from the E2 ubiquitin-conjugating enzyme to the target protein either by forming an E3-ubiquitin thioester intermediate in the case of HECT E3 ubiquitin ligases or by facilitating the transfer of ubiquitin directly from the E2 to the substrate for RING finger E3 ubiquitin ligases. The cullin subunit Cull functions as a molecular scaffold that interacts at the amino terminus with the adaptor subunit Skpl (S-phase kinase-associated protein 1) and at the carboxyl terminus with a RING-finger protein Rbxl and a specific E2 enzyme or ubiquitin conjugating enzyme. The F-box protein β-TrCP function as the variable component that binds Skp1, through the F-box domain, and the substrate, through its WD40 motif.
Here, we show thatβ-TrCP interacts with TRF1 and promotes its ubiquition. We first identified 8 novel TRF1 interacting proteins from Hela cell lysates which stably express Flag-TRF1 using immunoprecipitation and protein mass spectrometry. We validated that TRF1 interacts withβ-TrCP in vivo. Overexpression ofβ-TrCP can decrease the expression of TRF1. Moreover, we carried out in vivo ubiquitination assay and the results showed thatβ-TrCP can promote ubiquitination of TRF1 in vivo. Further studies showed that overexpression ofβ-TrCP but not itsΔF-box mutant enhances the ubiquitination of TRF1 and promotes the turnover of endogenous TRF1, whereas depletion ofβ-TrCP decreases TRF1 degradation. Interestingly, we found in telomerase-negative cells, PML3 can specially protect TRF1 from degradation caused byβ-TrCP, andβ-TrCP can negatively regulate the APBs formation through interacting with TRF1. These findings indicate thatβ-TrCP is a novel E3 ligase for TRF1 and may facilitate APBs formation via regulating ubiquitination and degradation of TRF1.
Human PinX1 was originally identified as a novel TRF1 interacting protein. PinXl is a widely expressed protein which notably contains two special domains: G-patch domain, which usually in RNA-binding proteins, and the telomerase inhibitor domain (TID). Suppression of telomerase activity by PinX1 is mediated by its direct interaction with hTERT and hTR. However, whether Gno1p, the yeast homolog of human PinX1, can suppress the telomerase ability is controversial.In addition to its telomeric localization and telomerase inhibitory function, PinX1 can be found in the nucleoli of human telomerase positive cells and enhance the accumulation of TRF1 in nucleolus. Moreover, our recent studies show that PinX1 can localize to chromosome periphery and outer plate of kinetochores during mitosis. Depletion of PinX1 results in lagging chromosome in mitosis and micronuclei in interphase. However, the precise regulatory mechanism of PinX1 remains elusive.
Here we show that Plkl is a novel interacting protein of PinX1. We performed a yeast two-hybrid assay to search its interacting protein using full-length human PinX1 cDNA as bait. In all total 1×106 clones, we identified 19 positive clones from human testis cDNA library. Nucleotide sequencing revealed that one of these interactors encodes the N terminus of Plkl (21-217 aa). Our biochemical experiments demonstrate that Plkl can interact with and phosphorylate PinX1 in vitro and in vivo. Indirect immunofluorescence staining shows that both Plkl and PinX1 can localize to spindle in mitosis. PinX1 binds to the N-terminal domain of Plk1 through its 92-254 domain. In vitro phosphorylation assay showed that PinX1 is a novel phosphorylation substrate of Plk1. The phosphopeptide of full-length PinX1 was analyzed by MALDI-MS, and three serine and two threonine residues were identified. We generated PinX1 5A mutant which all five serines and threonines were replaced by alanine and phospho-mimicking PinXl mutant which five serines and threonines were replaced by asparagine. Overexpression of wild-type Plkl but not its kinase-defective mutant interrupts the stability of PinX1 through regulating ubiquitin-associated proteolytic degradation of PinX1. Depletion of Plkl by siRNA increases the protein level of PinX1. We validated that Plkl-associated phosphorylation of PinX1 is essential for Plkl-mediated degradation of PinX1. Moreover, expression of GFP-PinX1 resulted in a significant increase in cells bearing misaligned chromosomes. Our studies demonstrate that Plkl interacts with PinX1 and regulates its stability by phosphorylation and such phosphorylation of PinX1 by Plk1 is essential for faithful chromosome congression.
由于DNA末端复制问题的存在(即细胞每分裂一次端粒就丢失数十至数百个不等的碱基),大部分肿瘤细胞和永生化细胞株例如睾丸细胞,均通过端粒酶维持端粒长度的稳定,但有一小部分肿瘤细胞,是依靠端粒延伸替代机制的激活来维持自身端粒长度的稳定,而在ALT机制维持端粒长度的调节过程中,ALT相关PML小体起到至关重要的作用。研究表明,ALT机制的核心是端粒染色体的互换重组,这个互换重组的过程在APB发生且受到精确调控,之前有研究表明TRF1的SUMO化影响了APB的形成。我们课题组此前的研究亦表明,TRF1受PML3招募上PML小体,且PML3在维持APB的形成中起到关键作用,但关于TRF1定位于APB的具体调控机制还不清楚。
泛素-蛋白酶体途径是真核生物体内重要的蛋白降解途径之一。针对目标蛋白的泛素化降解是一个多步骤过程,Ub首先由E1激活酶激活,进而被转移到E2接合酶的活化胱氨酸上,再由一个特异的E3泛素连接酶将Ub从接合酶转移到靶蛋白上。其中,含有HECT结构域的E3连接酶能够和泛素形成硫酯中间体,进而直接催化靶蛋白的泛素化。而含有锌指环结构的E3连接酶则作为支架蛋白将E2接合酶与底物招募到一起,将Ub直接转移到底物上,其本身并不直接参与靶蛋白的泛素化。SCFβ-TrCP即是一种含有锌指结构的E3连接酶复合体,由四种核心亚基组成：Skp1、Cull,β-TrCP和Rbxl。其中Rbxl负责募集E2接合酶并催化亚基,Cull作为分子支架在其氨基端与Skpl结合,在羧基端和Rbxl以及E2接合酶相互作用。Rbx1和其他亚基之间的支架参与底物的选择,β-TrCP通过其F-box结构域与Skpl相互结合,并通过其WD40重复性序列特异性识别底物,多数情况下β-TrCP能够识别底物上的一个特殊的磷酸化氨基酸序列,但亦有报道称β-TrCP也能够识别非磷酸化蛋白。
本课题组通过体内免疫沉淀结合蛋白质质谱鉴定的方法,从稳定表达Flag-TRF1的Hela细胞中分离出了8个可能的TRF1相互作用蛋白,序列比对发现,β-TrCP有可能是一个新的TRFl结合蛋白质,我们通过一系列体内实验证实了β-TrCP能够与TRF1在体内相互作用,外源性过量表达β-TrCP能够导致TRF1的表达量降低,进一步研究显示,β-TrCP通过促进TRF1的泛素化降解调控TRF1的蛋白表达水平,并且这一调控功能依赖于β-TrCP的F-box结构域。令人意外的是,我们发现在端粒酶阴性细胞中,PML3可以保护TRF1不受β-TrCP的降解,过量表达β-TrCP能够调控APB的形成,而利用siRNA抑制内源性β-TrCP的表达,则使得APB数量明显减少,提示β-TrCP在调控APB的形成中起到重要作用。本次研究首次发现了TRF1是一个新的β-TrCP底物蛋白,并且证明了β-TrCP在APB形成的调控中起到重要作用,为进一步探讨APB的形成及调控机制提供了新的佐证及线索。
PinX1最初是作为一个新的TRF1相互作用蛋白,由Lu等在2001年首次报道,PinX1含有两个特殊的结构域：通常存在于RNA结合蛋白中的G-patch结构域以及端粒酶抑制结构域(TID)。PinX1是迄今为止发现的最强力的端粒酶抑制因子,PinX1的端粒酶抑制作用通过其本身与hTERT和hTR直接作用来实现,尽管如此,PinX1在酵母中的同源物Gnolp是否具有端粒酶抑制作用目前还存在争议。除了端粒定位以及端粒酶抑制作用外,PinX1还被发现在端粒酶阳性细胞株中能够定位于核仁,并且能够增强TRF1在核仁的聚集,表明PinX1还具有其他功能。我们课题组在前期的研究中,意外的发现在有丝分裂期,PinX1能够定位于染色体周边以及动点外层,在有丝分裂期,SiRNA敲除PinX1够导致滞后染色体的出现,在间期,敲除PinX1能够导致小核细胞的增多,但关于PinX1具体的调控机制仍不清楚。
在前期工作的基础上,本课题组利用酵母双杂交的方法来寻找新的PinX1的相互作用蛋白,我们成功的从人睾丸cDNA文库中筛选到了19个阳性克隆,通过序列比对,我们发现Plk1可能是一个新的PinX1的相互作用蛋白。通过体内体外实验,进一步证实了PinX1与Plk1之间的相互作用。免疫荧光实验显示：PinXl与Plk1在有丝分裂期共定位于纺锤体上。PinX1通过其92-254段与Plk1的激酶结构域直接结合。此外,我们通过体外磷酸化的方法鉴定出PinX1是一个新的Plk1的磷酸化底物蛋白。通过蛋白质磷酸化质谱技术,我们得到了潜在的PinX1的磷酸化位点,我们构建了PinX1的非磷酸化突变体和模拟磷酸化突变体,并在体外磷酸化实验中得到了验证。进一步的研究表明,PinX1在体内能发生泛素化修饰,Plk1对PinX1的磷酸化调控PinX1的蛋白表达量变化。通过流式细胞术和免疫荧光的方法,我们发现外源转染PinX1的非磷酸化突变体可导致细胞阻滞到有丝分裂期,并且导致错误染色体的排列。综上,本部分研究证实了PinX1是一个新的Plk1的底物蛋白,Plk1通过磷酸化PinX1促进PinX1的泛素化降解,更进一步,我们发现了PinX1的磷酸化对于细胞的有丝分裂正常进行是必须的。通过以上研究,我们阐明了PinX1的磷酸化修饰的具体机制和功能,为深入阐明细胞有丝分裂过程的调控机制提供了新的实验证据和思路。
综上所述,本项研究分为二个部分,第一部分,我们首次发现了β-TrCP与TRF1之间的相互作用,β-TrCP是一个新的负责TRF1泛素化降解的泛素-蛋白质连接酶,在端粒酶阴性细胞株中,PML3能够特异性的保护TRF1不受β-TrCP的降解,且β-TrCP在调控APB的形成中起重要作用。为深入探讨APB的形成及调控机制提供了新的佐证和线索。本课题的第二部分研究,首次发现了PinX1与Plk1的相互作用,PinX1是Plkl的磷酸化底物蛋白,Plk1通过磷酸化PinX1促进PinX1的泛素化降解,并且PinX1的磷酸化对于细胞有丝分裂的正常进行是必须的,这为深入研究细胞有丝分裂的调控机制提供了新的实验证据和思路。
Telomere is a specialized nucleoprotein complex which contains repetitive G-rich DNA sequences and partner proteins to protect the chromosomal ends from degradation and to prevent the chromosomal end-to-end fusion. Dysfunction of telomere leads to genome instability and higher incidence of cancer in the aged cells. Although the maintenance of telomere length is mainly performed by a specific reverse transcriptase named telomerase in most malignant cancer cells, telomere-associated proteins are essential for adequate maintenance of telomeric DNA. Telomere-associated proteins directly and indirectly interact with telomeric DNA and contribute to telomere structure and function. Moreover, mounting evidence suggests that telomeric associated proteins may play important roles in cell cycle progression. For examble, expression level of TRF1 is regulated during the cell cycle, besides, it is reported that TRF1 can interact with microtubule, EB1 and some spindle checkpoint proteins such as Madl and Nek2. These results indicate that TRF1 and its partner telomeric interacting proteins may function as important signals in cell cycle.
The ubiquitin-proteasome system, the most important protein degradation pathway in eukaryotic cells, regulates a host of critical cellular functions such as cell cycle progression and apoptosis through mediating the selective and time-dependent degradation of short-lived regulatory proteins. Previous studies reported that TRF1 can be ubiquitiated by some E3 ligases such as FBX4 and RLIM, indicating the importance of ubiquitin-proteasome system in regulating telomeric associated proteins.
Telomeres can be shorten by 50-150 base pairs (bp) per cell division owing to the end-replication problem of the chromosome, which leads to replicative senescence when the telomere length reaches a critical point in normal somatic cells. Most cancer cells elongate there telomeres by activating telomerase. However, there are some cancer cells cannot activate telomerase and use telomere homologous recombination to elongate telomeres, a mechanism termed alternative lengthening of telomeres (ALT). The presence of ALT-associated PML bodies (APBs) is a hallmark of ALT cells. It has been suggested that APBs may have an integral role in the ALT mechanism, but the precise mechanism of APBs formation remains to be elucidated. Previous studies revealed that TRFl and its sumoylation is essential for the formation of APBs. Our recent study also showed that PML3 can assist the recruitment of TRF1 to APBs and is essential for APBs formation, but the detailed mechanism of the APBs formation is unknown.
The ubiquitin-proteasome system is one of the most important protein degradation pathway in eukaryotic cells. Ubiquitination of target proteins is a multistep process. After activation by E1 enzyme, ubiqui tin is transferred to an active cystine of a ubiquitin-conjugating enzyme (E2). A ubiquitin ligase (E3) then transfers ubiquitin from the E2 ubiquitin-conjugating enzyme to the target protein either by forming an E3-ubiquitin thioester intermediate in the case of HECT E3 ubiquitin ligases or by facilitating the transfer of ubiquitin directly from the E2 to the substrate for RING finger E3 ubiquitin ligases. The cullin subunit Cull functions as a molecular scaffold that interacts at the amino terminus with the adaptor subunit Skpl (S-phase kinase-associated protein 1) and at the carboxyl terminus with a RING-finger protein Rbxl and a specific E2 enzyme or ubiquitin conjugating enzyme. The F-box protein β-TrCP function as the variable component that binds Skp1, through the F-box domain, and the substrate, through its WD40 motif.
Here, we show thatβ-TrCP interacts with TRF1 and promotes its ubiquition. We first identified 8 novel TRF1 interacting proteins from Hela cell lysates which stably express Flag-TRF1 using immunoprecipitation and protein mass spectrometry. We validated that TRF1 interacts withβ-TrCP in vivo. Overexpression ofβ-TrCP can decrease the expression of TRF1. Moreover, we carried out in vivo ubiquitination assay and the results showed thatβ-TrCP can promote ubiquitination of TRF1 in vivo. Further studies showed that overexpression ofβ-TrCP but not itsΔF-box mutant enhances the ubiquitination of TRF1 and promotes the turnover of endogenous TRF1, whereas depletion ofβ-TrCP decreases TRF1 degradation. Interestingly, we found in telomerase-negative cells, PML3 can specially protect TRF1 from degradation caused byβ-TrCP, andβ-TrCP can negatively regulate the APBs formation through interacting with TRF1. These findings indicate thatβ-TrCP is a novel E3 ligase for TRF1 and may facilitate APBs formation via regulating ubiquitination and degradation of TRF1.
Human PinX1 was originally identified as a novel TRF1 interacting protein. PinXl is a widely expressed protein which notably contains two special domains: G-patch domain, which usually in RNA-binding proteins, and the telomerase inhibitor domain (TID). Suppression of telomerase activity by PinX1 is mediated by its direct interaction with hTERT and hTR. However, whether Gno1p, the yeast homolog of human PinX1, can suppress the telomerase ability is controversial.In addition to its telomeric localization and telomerase inhibitory function, PinX1 can be found in the nucleoli of human telomerase positive cells and enhance the accumulation of TRF1 in nucleolus. Moreover, our recent studies show that PinX1 can localize to chromosome periphery and outer plate of kinetochores during mitosis. Depletion of PinX1 results in lagging chromosome in mitosis and micronuclei in interphase. However, the precise regulatory mechanism of PinX1 remains elusive.
Here we show that Plkl is a novel interacting protein of PinX1. We performed a yeast two-hybrid assay to search its interacting protein using full-length human PinX1 cDNA as bait. In all total 1×106 clones, we identified 19 positive clones from human testis cDNA library. Nucleotide sequencing revealed that one of these interactors encodes the N terminus of Plkl (21-217 aa). Our biochemical experiments demonstrate that Plkl can interact with and phosphorylate PinX1 in vitro and in vivo. Indirect immunofluorescence staining shows that both Plkl and PinX1 can localize to spindle in mitosis. PinX1 binds to the N-terminal domain of Plk1 through its 92-254 domain. In vitro phosphorylation assay showed that PinX1 is a novel phosphorylation substrate of Plk1. The phosphopeptide of full-length PinX1 was analyzed by MALDI-MS, and three serine and two threonine residues were identified. We generated PinX1 5A mutant which all five serines and threonines were replaced by alanine and phospho-mimicking PinXl mutant which five serines and threonines were replaced by asparagine. Overexpression of wild-type Plkl but not its kinase-defective mutant interrupts the stability of PinX1 through regulating ubiquitin-associated proteolytic degradation of PinX1. Depletion of Plkl by siRNA increases the protein level of PinX1. We validated that Plkl-associated phosphorylation of PinX1 is essential for Plkl-mediated degradation of PinX1. Moreover, expression of GFP-PinX1 resulted in a significant increase in cells bearing misaligned chromosomes. Our studies demonstrate that Plkl interacts with PinX1 and regulates its stability by phosphorylation and such phosphorylation of PinX1 by Plk1 is essential for faithful chromosome congression.
引文
1. Blasco MA, Lee HW, Hande MP, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 1997; 91:25-34.
2. Smogorzewska A, de Lange T. Regulation of telomerase by telomeric proteins. Annu Rev Biochem 2004; 73:177-208.
3. Harrington L. Making the most of a little:dosage effects in eukaryotic telomere length maintenance. Chromosome Res 2005; 13:493-504.
4. Chong L, van Steensel B, Broccoli D, et al. A human telomeric protein. Science 1995; 270:1663-7.
5. Cerone MA, Autexier C, Londono-Vallejo JA, Bacchetti S. A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT. Oncogene 2005; 24:7893-901.
6. de Lange T. Shelterin:the protein complex that shapes and safeguards human telomeres. Genes Dev 2005; 19:2100-10.
7. O'Connor MS, Safari A, Xin H, Liu D, Songyang Z. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc Natl Acad Sci U S A 2006; 103:11874-9.
8. Liu D, O'Connor MS, Qin J, Songyang Z. Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem 2004; 279:51338-42.
9. Smogorzewska A, van Steensel B, Bianchi A, et al. Control of human telomere length by TRF1 and TRF2. Mol Cell Biol 2000; 20:1659-68.
10. Griffith JD, Comeau L, Rosenfield S, et al. Mammalian telomeres end in a large duplex loop. Cell 1999; 97:503-14.
11. van Steensel B, de Lange T. Control of telomere length by the human telomeric protein TRF1. Nature 1997; 385:740-3.
12. Sandell LL, Zakian VA. Loss of a yeast telomere:arrest, recovery, and chromosome loss. Cell 1993; 75:729-39.
13. Kirk KE, Harmon BP, Reichardt IK, Sedat JW, Blackburn EH. Block in anaphase chromosome separation caused by a telomerase template mutation. Science 1997; 275:1478-81.
14. Ahmad K, Golic KG. Telomere loss in somatic cells of Drosophila causes cell cycle arrest and apoptosis. Genetics 1999; 151:1041-51.
15. Kishi S, Zhou XZ, Ziv Y, et al. Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks. J Biol Chem 2001; 276:29282-91.
16. Iwano T, Tachibana M, Reth M, Shinkai Y. Importance of TRF1 for functional telomere structure. J Biol Chem 2004; 279:1442-8.
17. Nakamura M, Zhou XZ, Kishi S, Lu KP. Involvement of the telomeric protein Pin2/TRF1 in the regulation of the mitotic spindle. FEBS Lett 2002; 514:193-8.
18. Nakamura M, Zhou XZ, Kishi S, Kosugi I, Tsutsui Y, Lu KP. A specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle. Curr Biol 2001; 11:1512-6.
19. Zhu Q, Meng L, Hsu JK, Lin T, Teishima J, Tsai RY. GNL3L stabilizes the TRF1 complex and promotes mitotic transition. J Cell Biol 2009; 185:827-39.
20. Karlseder J, Kachatrian L, Takai H, et al. Targeted deletion reveals an essential function for the telomere length regulator Trf1. Mol Cell Biol 2003; 23:6533-41.
21. Chang W, Dynek JN, Smith S. TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes Dev 2003; 17:1328-33.
22. Cristofari G, Lingner J. Telomere length homeostasis requires that telomerase levels are limiting. Embo J 2006; 25:565-74.
23. Lee TH, Perrem K, Harper JW, Lu KP, Zhou XZ. The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance. J Biol Chem 2006; 281:759-68.
24. Seki A, Coppinger JA, Du H, Jang CY, Yates JR,3rd, Fang G. Plk1- and beta-TrCP-dependent degradation of Bora controls mitotic progression. J Cell Biol 2008; 181:65-78.
25. Kim MK, Kang MR, Nam HW, Bae YS, Kim YS, Chung IK. Regulation of telomeric repeat binding factor 1 binding to telomeres by casein kinase 2-mediated phosphorylation. J Biol Chem 2008; 283:14144-52.
26. Wu ZQ, Yang X, Weber G, Liu X. Plk1 phosphorylation of TRF1 is essential for its binding to telomeres. J Biol Chem 2008; 283:25503-13.
27. Smith S, de Lange T. Tankyrase promotes telomere elongation in human cells. Curr Biol 2000; 10: 1299-302.
28. Cook BD, Dynek JN, Chang W, Shostak G, Smith S. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol 2002; 22:332-42.
29. Smith S, Giriat I, Schmitt A, de Lange T. Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 1998; 282:1484-7.
30. Kim SH, Kaminker P, Campisi J. TIN2, a new regulator of telomere length in human cells. Nat Genet 1999; 23:405-12.
31. Ye JZ, de Lange T. TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat Genet 2004; 36:618-23.
32. Her YR, Chung IK. Ubiquitin Ligase RLIM Modulates Telomere Length Homeostasis through a Proteolysis of TRF1. J Biol Chem 2009; 284:8557-66.
33. Yu J, Lan J, Wang C, et al. PML3 interacts with TRF1 and is essential for ALT-associated PML bodies assembly in U2OS cells. Cancer Lett; 291:177-86.
1. Colgin L, Reddel R. Telomere biology:a new player in the end zone. Curr Biol 2004; 14:R901-2.
2. Smogorzewska A, de Lange T. Regulation of telomerase by telomeric proteins. Annu Rev Biochem 2004; 73:177-208.
3. de Lange T. Shelterin:the protein complex that shapes and safeguards human telomeres. Genes Dev 2005; 19:2100-10.
4. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet 2008; 42: 301-34.
5. De Boeck G, Forsyth RG, Praet M, Hogendoorn PC. Telomere-associated proteins:cross-talk between telomere maintenance and telomere-lengthening mechanisms. J Pathol 2009; 217:327-44.
6. Prime G, Markie D. The telomere repeat binding protein Trfl interacts with the spindle checkpoint protein Mad1 and Nek2 mitotic kinase. Cell Cycle 2005; 4:121-4.
7. Nakamura M, Zhou XZ, Kishi S, Kosugi I, Tsutsui Y, Lu KP. A specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle. Curr Biol 2001; 11:1512-6.
8. Zhou XZ, Perrem K, Lu KP. Role of Pin2/TRF1 in telomere maintenance and cell cycle control. J Cell Biochem 2003; 89:19-37.
9. Zhu Q, Meng L, Hsu JK, Lin T, Teishima J, Tsai RY. GNL3L stabilizes the TRF1 complex and promotes mitotic transition. J Cell Biol 2009; 185:827-39.
10. Zhou XZ, Lu KP. The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell 2001; 107:347-59.
11. Banik SS, Counter CM. Characterization of interactions between PinX1 and human telomerase subunits hTERT and hTR. J Biol Chem 2004; 279:51745-8.
12. Guglielmi B, Werner M. The yeast homolog of human PinX1 is involved in rRNA and small nucleolar RNA maturation, not in telomere elongation inhibition. J Biol Chem 2002; 277:35712-9.
13. Yoo JE, Oh BK, Park YN. Human PinX1 mediates TRF1 accumulation in nucleolus and enhances TRF1 binding to telomeres. J Mol Biol 2009; 388:928-40.
14. Yuan K, Li N, Jiang K, et al. PinX1 is a novel microtubule-binding protein essential for accurate chromosome segregation. J Biol Chem 2009; 284:23072-82.
15. Li N, Yuan K, Yan F, et al.PinX1 is recruited to the mitotic chromosome periphery by Nucleolin and facilitates chromosome congression. Biochem Biophys Res Commun 2009; 384:76-81.
16. van Vugt MA, Medema RH. Getting in and out of mitosis with Polo-like kinase-1. Oncogene 2005; 24:2844-59.
17. Petronczki M, Lenart P, Peters JM. Polo on the Rise-from Mitotic Entry to Cytokinesis with Plkl. Dev Cell 2008; 14:646-59.
18. Lowery DM, Lim D, Yaffe MB. Structure and function of Polo-like kinases. Oncogene 2005; 24: 248-59.
19. Dai W, Wang X. Grabbing Plkl by the PBD. Mol Cell 2006; 24:489-90.
20. Wu ZQ, Yang X, Weber G, Liu X. Plkl phosphorylation of TRF1 is essential for its binding to telomeres. J Biol Chem 2008; 283:25503-13.
21. Nishiyama A, Muraki K, Saito M, Ohsumi K, Kishimoto T, Ishikawa F. Cell-cycle-dependent Xenopus TRF1 recruitment to telomere chromatin regulated by Polo-like kinase. Embo J 2006; 25: 575-84.
22. Mamely I, van Vugt MA, Smits VA, et al. Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery. Curr Biol 2006; 16:1950-5.
23. Moshe Y, Boulaire J, Pagano M, Hershko A. Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proc Natl Acad Sci U S A 2004; 101:7937-42.
1. Blasco MA, Lee HW, Hande MP, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 1997; 91:25-34.
2. Smogorzewska A, de Lange T. Regulation of telomerase by telomeric proteins. Annu Rev Biochem 2004; 73:177-208.
3. Harrington L. Making the most of a little:dosage effects in eukaryotic telomere length maintenance. Chromosome Res 2005; 13:493-504.
4. Chong L, van Steensel B, Broccoli D, et al. A human telomeric protein. Science 1995; 270:1663-7.
5. Cerone MA, Autexier C, Londono-Vallejo JA, Bacchetti S. A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT. Oncogene 2005; 24:7893-901.
6. de Lange T. Shelterin:the protein complex that shapes and safeguards human telomeres. Genes Dev 2005; 19:2100-10.
7. O'Connor MS, Safari A, Xin H, Liu D, Songyang Z. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc Natl Acad Sci U S A 2006; 103:11874-9.
8. Liu D, O'Connor MS, Qin J, Songyang Z. Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem 2004; 279:51338-42.
9. Smogorzewska A, van Steensel B, Bianchi A, et al. Control of human telomere length by TRF1 and TRF2. Mol Cell Biol 2000; 20:1659-68.
10. Griffith JD, Comeau L, Rosenfield S, et al. Mammalian telomeres end in a large duplex loop. Cell 1999; 97:503-14.
11. van Steensel B, de Lange T. Control of telomere length by the human telomeric protein TRF1. Nature 1997; 385:740-3.
12. Sandell LL, Zakian VA. Loss of a yeast telomere:arrest, recovery, and chromosome loss. Cell 1993; 75:729-39.
13. Kirk KE, Harmon BP, Reichardt IK, Sedat JW, Blackburn EH. Block in anaphase chromosome separation caused by a telomerase template mutation. Science 1997; 275:1478-81.
14. Ahmad K, Golic KG. Telomere loss in somatic cells of Drosophila causes cell cycle arrest and apoptosis. Genetics 1999; 151:1041-51.
15. Kishi S, Zhou XZ, Ziv Y, et al. Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks. J Biol Chem 2001; 276:29282-91.
16. Iwano T, Tachibana M, Reth M, Shinkai Y. Importance of TRF1 for functional telomere structure. J Biol Chem 2004; 279:1442-8.
17. Nakamura M, Zhou XZ, Kishi S, Lu KP. Involvement of the telomeric protein Pin2/TRF1 in the regulation of the mitotic spindle. FEBS Lett 2002; 514:193-8.
18. Nakamura M, Zhou XZ, Kishi S, Kosugi I, Tsutsui Y, Lu KP. A specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle. Curr Biol 2001; 11:1512-6.
19. Zhu Q, Meng L, Hsu JK, Lin T, Teishima J, Tsai RY. GNL3L stabilizes the TRF1 complex and promotes mitotic transition. J Cell Biol 2009; 185:827-39.
20. Karlseder J, Kachatrian L, Takai H, et al. Targeted deletion reveals an essential function for the telomere length regulator Trf1. Mol Cell Biol 2003; 23:6533-41.
21. Chang W, Dynek JN, Smith S. TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes Dev 2003; 17:1328-33.
22. Cristofari G, Lingner J. Telomere length homeostasis requires that telomerase levels are limiting. Embo J 2006; 25:565-74.
23. Lee TH, Perrem K, Harper JW, Lu KP, Zhou XZ. The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance. J Biol Chem 2006; 281: 759-68.
24. Seki A, Coppinger JA, Du H, Jang CY, Yates JR,3rd, Fang G. Plkl- and beta-TrCP-dependent degradation of Bora controls mitotic progression. J Cell Biol 2008; 181:65-78.
25. Kim MK, Kang MR, Nam HW, Bae YS, Kim YS, Chung IK. Regulation of telomeric repeat binding factor 1 binding to telomeres by casein kinase 2-mediated phosphorylation. J Biol Chem 2008; 283: 14144-52.
26. Wu ZQ, Yang X, Weber G, Liu X. Plkl phosphorylation of TRF1 is essential for its binding to telomeres. J Biol Chem 2008; 283:25503-13.
27. Smith S, de Lange T. Tankyrase promotes telomere elongation in human cells. Curr Biol 2000; 10: 1299-302.
28. Cook BD, Dynek JN, Chang W, Shostak G, Smith S. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol 2002; 22:332-42.
29. Smith S, Giriat I, Schmitt A, de Lange T. Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 1998; 282:1484-7.
30. Kim SH, Kaminker P, Campisi J. TIN2, a new regulator of telomere length in human cells. Nat Genet 1999; 23:405-12.
31. Ye JZ, de Lange T. TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat Genet 2004; 36:618-23.
32. Her YR, Chung IK. Ubiquitin Ligase RLIM Modulates Telomere Length Homeostasis through a Proteolysis of TRF1. J Biol Chem 2009; 284:8557-66.
33. Yu J, Lan J, Wang C, et al. PML3 interacts with TRF1 and is essential for ALT-associated PML bodies assembly in U2OS cells. Cancer Lett; 291:177-86.
34. Colgin L, Reddel R. Telomere biology:a new player in the end zone. Curr Biol 2004; 14:R901-2.
35. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet 2008; 42: 301-34.
36. De Boeck G, Forsyth RG, Praet M, Hogendoorn PC. Telomere-associated proteins:cross-talk between telomere maintenance and telomere-lengthening mechanisms. J Pathol 2009; 217:327-44.
37. Prime G, Markie D. The telomere repeat binding protein Trfl interacts with the spindle checkpoint protein Mad1 and Nek2 mitotic kinase. Cell Cycle 2005; 4:121-4.
38. Zhou XZ, Perrem K, Lu KP. Role of Pin2/TRF1 in telomere maintenance and cell cycle control. J Cell Biochem 2003; 89:19-37.
39. Zhou XZ, Lu KP. The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell 2001; 107:347-59.
40. Banik SS, Counter CM. Characterization of interactions between PinX1 and human telomerase subunits hTERT and hTR. J Biol Chem 2004; 279:51745-8.
41. Guglielmi B, Werner M. The yeast homolog of human PinX1 is involved in rRNA and small nucleolar RNA maturation, not in telomere elongation inhibition. J Biol Chem 2002; 277:35712-9.
42. Yoo JE, Oh BK, Park YN. Human PinX1 mediates TRF1 accumulation in nucleolus and enhances TRF1 binding to telomeres. J Mol Biol 2009; 388:928-40.
43. Yuan K, Li N, Jiang K, et al. PinX1 is a novel microtubule-binding protein essential for accurate chromosome segregation. J Biol Chem 2009; 284:23072-82.
44. Li N, Yuan K, Yan F, et al. PinX1 is recruited to the mitotic chromosome periphery by Nucleolin and facilitates chromosome congression. Biochem Biophys Res Commun 2009; 384:76-81.
45. van Vugt MA, Medema RH. Getting in and out of mitosis with Polo-like kinase-1. Oncogene 2005; 24:2844-59.
46. Petronczki M, Lenart P, Peters JM. Polo on the Rise-from Mitotic Entry to Cytokinesis with Plkl. Dev Cell 2008; 14:646-59.
47. Lowery DM, Lim D, Yaffe MB. Structure and function of Polo-like kinases. Oncogene 2005; 24: 248-59.
48. Dai W, Wang X. Grabbing Plkl by the PBD. Mol Cell 2006; 24:489-90.
49. Nishiyama A, Muraki K, Saito M, Ohsumi K, Kishimoto T, Ishikawa F. Cell-cycle-dependent Xenopus TRF1 recruitment to telomere chromatin regulated by Polo-like kinase. Embo J 2006; 25: 575-84.
50. Mamely I, van Vugt MA, Smits VA, et al. Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery. Curr Biol 2006; 16:1950-5.
51. Moshe Y, Boulaire J, Pagano M, Hershko A. Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proc Natl Acad Sci U S A 2004; 101:7937-42.
52. Sunkel CE, Glover DM. polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J Cell Sci 1988; 89 (Pt 1):25-38.
53. Llamazares S, Moreira A, Tavares A, et al. polo encodes a protein kinase homolog required for mitosis in Drosophila. Genes Dev 1991; 5:2153-65.
54. Glover DM, Hagan IM, Tavares AA. Polo-like kinases:a team that plays throughout mitosis. Genes Dev 1998; 12:3777-87.
55. Barr FA, Sillje HH, Nigg EA. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol 2004; 5:429-40.
56. Andrysik Z, Bernstein WZ, Deng L, et al. The novel mouse Polo-like kinase 5 responds to DNA damage and localizes in the nucleolus. Nucleic Acids Res 2010; 38:2931-43.
57. Clay FJ, McEwen SJ, Bertoncello I, Wilks AF, Dunn AR. Identification and cloning of a protein kinase-encoding mouse gene, Plk, related to the polo gene of Drosophila. Proc Natl Acad Sci U S A 1993; 90:4882-6.
58. van de Weerdt BC, Medema RH. Polo-like kinases:a team in control of the division. Cell Cycle 2006; 5:853-64.
59. Takaki T, Trenz K, Costanzo V, Petronczki M. Polo-like kinase 1 reaches beyond mitosis--cytokinesis, DNA damage response, and development. Curr Opin Cell Biol 2008; 20: 650-60.
60. Archambault V, Glover DM. Polo-like kinases:conservation and divergence in their functions and regulation. Nat Rev Mol Cell Biol 2009; 10:265-75.
61. Cogswell JP, Brown CE, Bisi JE, Neill SD. Dominant-negative polo-like kinase 1 induces mitotic catastrophe independent of cdc25C function. Cell Growth Differ 2000; 11:615-23.
62. Spankuch-Schmitt B, Wolf G, Solbach C, et al. Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells. Oncogene 2002; 21: 3162-71.
63. Spankuch-Schmitt B, Bereiter-Hahn J, Kaufmann M, Strebhardt K. Effect of RNA silencing of polo-like kinase-1 (PLK1) on apoptosis and spindle formation in human cancer cells. J Natl Cancer Inst 2002;94:1863-77.
64. Liu X, Erikson RL. Activation of Cdc2/cyclin B and inhibition of centrosome amplification in cells depleted of Plk 1 by siRNA. Proc Natl Acad Sci U S A 2002; 99:8672-6.
65. Strebhardt K, Ullrich A. Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer 2006; 6: 321-30.
66. Strebhardt K, Ullrich A. Paul Ehrlich's magic bullet concept:100 years of progress. Nat Rev Cancer 2008; 8:473-80.
67. Schoffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist 2009; 14:559-70.
68. McInnes C, Mezna M, Fischer PM. Progress in the discovery of polo-like kinase inhibitors. Curr Top Med Chem 2005; 5:181-97.
69. Xie S, Wang Q, Wu H, et al. Reactive oxygen species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like kinase-3. J Biol Chem 2001; 276:36194-9.
70. Xie S, Wu H, Wang Q, et al. Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway. J Biol Chem 2001; 276:43305-12.
71. Shimizu-Yoshida Y, Sugiyama K, Rogounovitch T, et al. Radiation-inducible hSNK gene is transcriptionally regulated by p53 binding homology element in human thyroid cells. Biochem Biophys Res Commun 2001; 289:491-8.
72. Holtrich U, Wolf G, Brauninger A, et al. Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors. Proc Natl Acad Sci U S A 1994; 91:1736-40.
73. Lu LY, Wood JL, Minter-Dykhouse K, et al. Polo-like kinase 1 is essential for early embryonic development and tumor suppression. Mol Cell Biol 2008; 28:6870-6.
74. Kitada K, Johnson AL, Johnston LH, Sugino A. A multicopy suppressor gene of the Saccharomyces cerevisiae G1 cell cycle mutant gene dbf4 encodes a protein kinase and is identified as CDC5. Mol Cell Biol 1993; 13:4445-57.
75. Ohkura H, Hagan IM, Glover DM. The conserved Schizosaccharomyces pombe kinase plol, required to form a bipolar spindle, the actin ring, and septum, can drive septum formation in G1 and G2 cells. Genes Dev 1995; 9:1059-73.
76. Lowery DM, Clauser KR, Hjerrild M, et al. Proteomic screen defines the Polo-box domain interactome and identifies Rock2 as a Plk1 substrate. EMBO J 2007; 26:2262-73.
77. Lee KS, Grenfell TZ, Yarm FR, Erikson RL. Mutation of the polo-box disrupts localization and mitotic functions of the mammalian polo kinase Plk. Proc Natl Acad Sci U S A 1998; 95:9301-6.
78. van de Weerdt BC, Littler DR, Klompmaker R, et al. Polo-box domains confer target specificity to the Polo-like kinase family. Biochim Biophys Acta 2008; 1783:1015-22.
79. Seong YS, Kamijo K, Lee JS, et al. A spindle checkpoint arrest and a cytokinesis failure by the dominant-negative polo-box domain of Plkl in U-2 OS cells. J Biol Chem 2002; 277:32282-93.
80. Song S, Grenfell TZ, Garfield S, Erikson RL, Lee KS. Essential function of the polo box of Cdc5 in subcellular localization and induction of cytokinetic structures. Mol Cell Biol 2000; 20:286-98.
81. Neef R, Preisinger C, Sutcliffe J, et al. Phosphorylation of mitotic kinesin-like protein 2 by polo-like kinase 1 is required for cytokinesis. J Cell Biol 2003; 162:863-75.
82. Kang YH, Park JE, Yu LR, et al. Self-regulated Plkl recruitment to kinetochores by the Plk1-PBIP1 interaction is critical for proper chromosome segregation. Mol Cell 2006; 24:409-22.
83. Neef R, Gruneberg U, Kopajtich R, et al. Choice of Plkl docking partners during mitosis and cytokinesis is controlled by the activation state of Cdkl. Nat Cell Biol 2007; 9:436-44.
84. Jang YJ, Lin CY, Ma S, Erikson RL. Functional studies on the role of the C-terminal domain of mammalian polo-like kinase. Proc Natl Acad Sci U S A 2002; 99:1984-9.
85. Elia AE, Rellos P, Haire LF, et al. The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain. Cell 2003; 115:83-95.
86. Golsteyn RM, Mundt KE, Fry AM, Nigg EA. Cell cycle regulation of the activity and subcellular localization of Plk1, a human protein kinase implicated in mitotic spindle function. J Cell Biol 1995; 129:1617-28.
87 Jang YJ, Ma S, Terada Y, Erikson RL. Phosphorylation of threonine 210 and the role of serine 137 in the regulation of mammalian polo-like kinase. J Biol Chem 2002; 277:44115-20.
88. Daub H, Olsen JV, Bairlein M, et al. Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell 2008; 31:438-48.
89. Qian YW, Erikson E, Maller JL. Purification and cloning of a protein kinase that phosphorylates and activates the polo-like kinase Plxl. Science 1998; 282:1701-4.
90. Kelm O, Wind M, Lehmann WD, Nigg EA. Cell cycle-regulated phosphorylation of the Xenopus polo-like kinase Plxl. J Biol Chem 2002; 277:25247-56.
91. Ellinger-Ziegelbauer H, Karasuyama H, Yamada E, Tsujikawa K, Todokoro K, Nishida E. Ste20-like kinase (SLK), a regulatory kinase for polo-like kinase (Plk) during the G2/M transition in somatic cells. Genes Cells 2000; 5:491-8.
92. Seki A, Coppinger JA, Jang CY, Yates JR, Fang G. Bora and the kinase Aurora a cooperatively activate the kinase Plkl and control mitotic entry. Science 2008; 320:1655-8.
93. Macurek L, Lindqvist A, Lim D, et al. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature 2008; 455:119-23.
94. Chan EH, Santamaria A, Sillje HH, Nigg EA. Plk1 regulates mitotic Aurora A function through betaTrCP-dependent degradation of hBora. Chromosoma 2008; 117:457-69.
95. Laoukili J, Kooistra MR, Bras A, et al. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat Cell Biol 2005; 7:126-36.
96. Major ML, Lepe R, Costa RH. Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. Mol Cell Biol 2004; 24:2649-61.
97. Fu Z, Malureanu L, Huang J, et al. Plkl-dependent phosphorylation of FoxMl regulates a transcriptional programme required for mitotic progression. Nat Cell Biol 2008; 10:1076-82.
98. Wang IC, Chen YJ, Hughes D, et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cksl) ubiquitin ligase. Mol Cell Biol 2005; 25:10875-94.
99. Ando K, Ozaki T, Yamamoto H, et al. Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation. J Biol Chem 2004; 279:25549-61.
100. Whibley C, Pharoah PD, Hollstein M. p53 polymorphisms:cancer implications. Nat Rev Cancer 2009; 9:95-107.
101. Vazquez A, Bond EE, Levine AJ, Bond GL. The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov 2008; 7:979-87.
102. Liu X, Erikson RL. Polo-like kinase (Plk) 1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci U S A 2003; 100:5789-94.
103. Yang X, Li H, Zhou Z, et al. Plkl-mediated phosphorylation of Topors regulates p53 stability. J Biol Chem 2009; 284:18588-92.
104. Weger S, Hammer E, Heilbronn R. Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo. FEBS Lett 2005; 579:5007-12.
105. Rajendra R, Malegaonkar D, Pungaliya P, et al. Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J Biol Chem 2004; 279:36440-4.
106. Koida N, Ozaki T, Yamamoto H, et al. Inhibitory role of Plkl in the regulation of p73-dependent apoptosis through physical interaction and phosphorylation. J Biol Chem 2008; 283:8555-63.
107. Soond SM, Barry SP, Melino G, Knight RA, Latchman DS, Stephanou A. p73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. Cell Cycle 2008; 7:1214-23.
108. Sur S, Pagliarini R, Bunz F, et al. A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc Natl Acad Sci U S A 2009; 106:3964-9.
109. zur Hausen H. Papillomaviruses and cancer:from basic studies to clinical application. Nat Rev Cancer 2002; 2:342-50.
110.Patel D, Incassati A, Wang N, McCance DJ. Human papillomavirus type 16 E6 and E7 cause polyploidy in human keratinocytes and up-regulation of G2-M-phase proteins. Cancer Res 2004; 64: 1299-306.
111.Incassati A, Patel D, McCance DJ. Induction of tetraploidy through loss of p53 and upregulation of Plkl by human papillomavirus type-16 E6. Oncogene 2006; 25:2444-51.
112.Meraldi P, Honda R, Nigg EA. Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53-/- cells. EMBO J 2002; 21:483-92.
113.Lin HR, Ting NS, Qin J, Lee WH. M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex. J Biol Chem 2003; 278: 35979-87.
114.Lee M, Daniels MJ, Venkitaraman AR. Phosphorylation of BRCA2 by the Polo-like kinase Plkl is regulated by DNA damage and mitotic progression. Oncogene 2004; 23:865-72.
115.Tsvetkov L, Xu X, Li J, Stern DF. Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody. J Biol Chem 2003; 278:8468-75.
116.Smits VA, Klompmaker R, Arnaud L, Rijksen G, Nigg EA, Medema RH. Polo-like kinase-1 is a target of the DNA damage checkpoint. Nat Cell Biol 2000; 2:672-6.
117.Syljuasen RG, Jensen S, Bartek J, Lukas J. Adaptation to the ionizing radiation-induced G2 checkpoint occurs in human cells and depends on checkpoint kinase 1 and Polo-like kinase 1 kinases. Cancer Res 2006; 66:10253-7.
118.Yamaguchi T, Goto H, Yokoyama T, et al. Phosphorylation by Cdkl induces Plkl-mediated vimentin phosphorylation during mitosis. J Cell Biol 2005; 171:431-6.
119.Liu L, Zhang M, Zou P. Expression of PLK1 and survivin in diffuse large B-cell lymphoma. Leuk Lymphoma 2007; 48:2179-83.
120. Yamamoto Y, Matsuyama H, Kawauchi S, et al. Overexpression of polo-like kinase 1 (PLK1) and chromosomal instability in bladder cancer. Oncology 2006; 70:231-7.
121. Liu L, Zhang M, Zou P. Polo-like kinase 1 as a new target for non-Hodgkin's lymphoma treatment. Oncology 2008; 74:96-103.
122. Kanaji S, Saito H, Tsujitani S, et al. Expression of polo-like kinase 1 (PLK1) protein predicts the survival of patients with gastric carcinoma. Oncology 2006; 70:126-33.
123. Jang YJ, Kim YS, Kim WH. Oncogenic effect of Polo-like kinase 1 expression in human gastric carcinomas. Int J Oncol 2006; 29:589-94.
124. Simmons DL, Neel BG, Stevens R, Evett G, Erikson RL. Identification of an early-growth-response gene encoding a novel putative protein kinase. Mol Cell Biol 1992; 12:4164-9.
125. Anger M, Kues WA, Klima J, et al. Cell cycle dependent expression of Plkl in synchronized porcine fetal fibroblasts. Mol Reprod Dev 2003; 65:245-53.
126. Warnke S, Kemmler S, Hames RS, et al. Polo-like kinase-2 is required for centriole duplication in mammalian cells. Curr Biol 2004; 14:1200-7.
127. Cizmecioglu O, Warnke S, Arnold M, Duensing S, Hoffmann I. Plk2 regulated centriole duplication is dependent on its localization to the centrioles and a functional polo-box domain. Cell Cycle 2008; 7:3548-55.
128. Ma S, Charron J, Erikson RL. Role of Plk2 (Snk) in mouse development and cell proliferation. Mol Cell Biol 2003; 23:6936-43.
129. Ma S, Liu MA, Yuan YL, Erikson RL. The serum-inducible protein kinase Snk is a G1 phase polo-like kinase that is inhibited by the calcium- and integrin-binding protein CIB. Mol Cancer Res 2003; 1:376-84.
130. Kauselmann G, Weiler M, Wulff P, et al. The polo-like protein kinases Fnk and Snk associate with a Ca(2+)- and integrin-binding protein and are regulated dynamically with synaptic plasticity. EMBO J 1999; 18:5528-39.
131. Burns TF, Fei P, Scata KA, Dicker DT, El-Deiry WS. Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (taxol)-exposed cells. Mol Cell Biol 2003; 23: 5556-71.
132. Tovar C, Rosinski J, Filipovic Z, et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer:implications for therapy. Proc Natl Acad Sci U S A 2006; 103:1888-93.
133. Syed N, Smith P, Sullivan A, et al. Transcriptional silencing of Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies. Blood 2006; 107:250-6.
134. Donohue PJ, Alberts GF, Guo Y, Winkles JA. Identification by targeted differential display of an immediate early gene encoding a putative serine/threonine kinase. J Biol Chem 1995; 270:10351-7.
135. Holtrich U, Wolf G, Yuan J, et al. Adhesion induced expression of the serine/threonine kinase Fnk in human macrophages. Oncogene 2000; 19:4832-9.
136. Ouyang B, Pan H, Lu L, et al. Human Prk is a conserved protein serine/threonine kinase involved in regulating M phase functions. J Biol Chem 1997; 272:28646-51.
137. Chase D, Feng Y, Hanshew B, Winkles JA, Longo DL, Ferris DK. Expression and phosphorylation of fibroblast-growth-factor-inducible kinase (Fnk) during cell-cycle progression. Biochem J 1998; 333 (Pt 3):655-60.
138. Bahassi el M, Conn CW, Myer DL, et al. Mammalian Polo-like kinase 3 (Plk3) is a multifunctional protein involved in stress response pathways. Oncogene 2002; 21:6633-40.
139. Zimmerman WC, Erikson RL. Polo-like kinase 3 is required for entry into S phase. Proc Natl Acad Sci U S A 2007;104:1847-52.
140. Wang Q, Xie S, Chen J, et al. Cell cycle arrest and apoptosis induced by human Polo-like kinase 3 is mediated through perturbation of microtubule integrity. Mol Cell Biol 2002; 22:3450-9.
141. Jiang N, Wang X, Jhanwar-Uniyal M, Darzynkiewicz Z, Dai W. Polo box domain of Plk3 functions as a centrosome localization signal, overexpression of which causes mitotic arrest, cytokinesis defects, and apoptosis. J Biol Chem 2006; 281:10577-82.
142. Yang F, Camp DG,2nd, Gritsenko MA, et al. Identification of a novel mitotic phosphorylation motif associated with protein localization to the mitotic apparatus. J Cell Sci 2007; 120:4060-70.
143. Ruan Q, Wang Q, Xie S, et al. Polo-like kinase 3 is Golgi localized and involved in regulating Golgi fragmentation during the cell cycle. Exp Cell Res 2004; 294:51-9.
144. Lopez-Sanchez I, Sanz-Garcia M, Lazo PA. Plk3 interacts with and specifically phosphorylates VRK1 in Ser342, a downstream target in a pathway that induces Golgi fragmentation. Mol Cell Biol 2009; 29:1189-201.
145. Sutterlin C, Hsu P, Mallabiabarrena A, Malhotra V. Fragmentation and dispersal of the pericentriolar Golgi complex is required for entry into mitosis in mammalian cells. Cell 2002; 109: 359-69.
146. Li B, Ouyang B, Pan H, et al. Prk, a cytokine-inducible human protein serine/threonine kinase whose expression appears to be down-regulated in lung carcinomas. J Biol Chem 1996; 271: 19402-8.
147. Conn CW, Hennigan RF, Dai W, Sanchez Y, Stambrook PJ. Incomplete cytokinesis and induction of apoptosis by overexpression of the mammalian polo-like kinase, Plk3. Cancer Res 2000; 60: 6826-31.
148. Zhou T, Chou JW, Simpson DA, et al. Profiles of global gene expression in ionizing-radiation-damaged human diploid fibroblasts reveal synchronization behind the G1 checkpoint in a G0-like state of quiescence. Environ Health Perspect 2006; 114:553-9.
149. Staib F, Robles Al, Varticovski L, et al. The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. Cancer Res 2005; 65:10255-64.
150. Dai W, Li Y, Ouyang B, et al. PRK, a cell cycle gene localized to 8p21, is downregulated in head and neck cancer. Genes Chromosomes Cancer 2000; 27:332-6.
151. Yang Y, Bai J, Shen R, et al. Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditions. Cancer Res 2008; 68: 4077-85.
152. Weichert W, Kristiansen G, Winzer KJ, et al. Polo-like kinase isoforms in breast cancer:expression patterns and prognostic implications. Virchows Arch 2005; 446:442-50.
153. Weichert W, Denkert C, Schmidt M, et al. Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma. Br J Cancer 2004; 90:815-21.
154. Fode C, Motro B, Yousefi S, Heffernan M, Dennis JW. Sak, a murine protein-serine/threonine kinase that is related to the Drosophila polo kinase and involved in cell proliferation. Proc Natl Acad SciUSA1994; 91:6388-92.
155. Fode C, Binkert C, Dennis JW. Constitutive expression of murine Sak-a suppresses cell growth and induces multinucleation. Mol Cell Biol 1996; 16:4665-72.
156. Hudson JW, Kozarova A, Cheung P, et al. Late mitotic failure in mice lacking Sak, a polo-like kinase. Curr Biol 2001; 11:441-6.
157. Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA. The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol 2005; 7:1140-6.
158. Bettencourt-Dias M, Rodrigues-Martins A, Carpenter L, et al. SAK/PLK4 is required for centriole duplication and flagella development. Curr Biol 2005; 15:2199-207.
159. Li J, Tan M, Li L, Pamarthy D, Lawrence TS, Sun Y. SAK, a new polo-like kinase, is transcriptionally repressed by p53 and induces apoptosis upon RNAi silencing. Neoplasia 2005; 7: 312-23.
160. Deloukas P, Schuler GD, Gyapay G, et al. A physical map of 30,000 human genes. Science 1998; 282:744-6.
161. Hammond C, Jeffers L, Carr BI, Simon D. Multiple genetic alterations,4q28, a new suppressor region, and potential gender differences in human hepatocellular carcinoma. Hepatology 1999; 29: 1479-85.
162. Macmillan JC, Hudson JW, Bull S, Dennis JW, Swallow CJ. Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer. Ann Surg Oncol 2001; 8:729-40.
163. Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 2004; 4:927-36.
164. Perez de Castro I, de Carcer G, Montoya G, Malumbres M. Emerging cancer therapeutic opportunities by inhibiting mitotic kinases. Curr Opin Pharmacol 2008; 8:375-83.
165. Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 2009; 8:547-66.
166. Lane HA, Nigg EA. Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plkl) in the functional maturation of mitotic centrosomes. J Cell Biol 1996; 135:1701-13.
167. Yuan J, Kramer A, Eckerdt F, Kaufmann M, Strebhardt K. Efficient internalization of the polo-box of polo-like kinase 1 fused to an Antennapedia peptide results in inhibition of cancer cell proliferation. Cancer Res 2002; 62:4186-90.
168. Spankuch B, Matthess Y, Knecht R, Zimmer B, Kaufmann M, Strebhardt K. Cancer inhibition in nude mice after systemic application of U6 promoter-driven short hairpin RNAs against PLK1. J Natl Cancer Inst 2004; 96:862-72.
169. Kappel S, Matthess Y, Zimmer B, Kaufmann M, Strebhardt K. Tumor inhibition by genomically integrated inducible RNAi-cassettes. Nucleic Acids Res 2006; 34:4527-36.
170. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298:1912-34.
171. Goldstein DM, Gray NS, Zarrinkar PP. High-throughput kinase profiling as a platform for drug discovery. Nat Rev Drug Discov 2008; 7:391-7.
172. Johnson EF, Stewart KD, Woods KW, Giranda VL, Luo Y. Pharmacological and functional comparison of the polo-like kinase family:insight into inhibitor and substrate specificity. Biochemistry 2007; 46:9551-63.
173. Kothe M, Kohls D, Low S, et al. Structure of the catalytic domain of human polo-like kinase 1. Biochemistry 2007; 46:5960-71.
174. Steegmaier M, Hoffmann M, Baum A, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol 2007; 17:316-22.
175. Wang HY, Cao ZX, Li LL, et al. Pharmacophore modeling and virtual screening for designing potential PLK1 inhibitors. Bioorg Med Chem Lett 2008; 18:4972-7.
176. McInnes C, Mazumdar A, Mezna M, et al. Inhibitors of Polo-like kinase reveal roles in spindle-pole maintenance. Nat Chem Biol 2006; 2:608-17.
177. Peters U, Cherian J, Kim JH, Kwok BH, Kapoor TM. Probing cell-division phenotype space and Polo-like kinase function using small molecules. Nat Chem Biol 2006; 2:618-26.
178. Santamaria A, Neef R, Eberspacher U, et al. Use of the novel Plkl inhibitor ZK-thiazolidinone to elucidate functions of Plkl in early and late stages of mitosis. Mol Biol Cell 2007; 18:4024-36.
179. Lansing TJ, McConnell RT, Duckett DR, et al. In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1. Mol Cancer Ther 2007; 6:450-9.
180. Baumann C, Korner R, Hofmann K, Nigg EA. PICH, a centromere-associated SNF2 family ATPase, is regulated by Plkl and required for the spindle checkpoint. Cell 2007; 128:101-14.
181. Sato Y, Onozaki Y, Sugimoto T, et al. Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors. Bioorg Med Chem Lett 2009; 19:4673-8.
182. Uckun FM, Dibirdik I, Qazi S, et al. Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK). Bioorg Med Chem 2007; 15:800-14.
183. Uckun FM. Chemosensitizing anti-cancer activity of LFM-A13, a leflunomide metabolite analog targeting polo-like kinases. Cell Cycle 2007; 6:3021-6.
184. Reindl W, Yuan J, Kramer A, Strebhardt K, Berg T. Inhibition of polo-like kinase 1 by blocking polo-box domain-dependent protein-protein interactions. Chem Biol 2008; 15:459-66.
185. Reindl W, Strebhardt K, Berg T. A high-throughput assay based on fluorescence polarization for inhibitors of the polo-box domain of polo-like kinase 1. Anal Biochem 2008; 383:205-9.
186. Hanisch A, Wehner A, Nigg EA, Sillje HH. Different Plkl functions show distinct dependencies on Polo-Box domain-mediated targeting. Mol Biol Cell 2006; 17:448-59.
187. Gali-Muhtasib H, Roessner A, Schneider-Stock R. Thymoquinone:a promising anti-cancer drug from natural sources. Int J Biochem Cell Biol 2006; 38:1249-53.
188. Kaseb AO, Chinnakannu K, Chen D, et al. Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer. Cancer Res 2007; 67:7782-8.
189. Watanabe N, Sekine T, Takagi M, et al. Deficiency in chromosome congression by the inhibition of Plkl polo box domain-dependent recognition. J Biol Chem 2009; 284:2344-53.
190. Abou-Karam M, Shier WT. Inhibition of oncogene product enzyme activity as an approach to cancer chemoprevention. Tyrosine-specific protein kinase inhibition by purpurogallin from Quercus sp. nutgall. Phytother Res 1999; 13:337-40.
191. Farnet CM, Wang B, Hansen M, et al. Human immunodeficiency virus type 1 cDNA integration: new aromatic hydroxylated inhibitors and studies of the inhibition mechanism. Antimicrob Agents Chemother 1998; 42:2245-53.
192. Jackson JR, Patrick DR, Dar MM, Huang PS. Targeted anti-mitotic therapies:can we improve on tubulin agents? Nat Rev Cancer 2007; 7:107-17.
193. Gumireddy K, Reddy MV, Cosenza SC, et al. ON01910, a non-ATP-competitive small molecule inhibitor of Plkl, is a potent anticancer agent. Cancer Cell 2005; 7:275-86.
194. Jimeno A, Li J, Messersmith WA, et al. Phase I study of ON 01910.Na, a novel modulator of the Polo-like kinase 1 pathway, in adult patients with solid tumors. J Clin Oncol 2008; 26:5504-10.
195. Jimeno A, Chan A, Cusatis G, et al. Evaluation of the novel mitotic modulator ON 01910.Na in pancreatic cancer and preclinical development of an ex vivo predictive assay. Oncogene 2009; 28: 610-8.
196. Tanaka H, Ohshima N, Ikenoya M, Komori K, Katoh F, Hidaka H. HMN-176, an active metabolite of the synthetic antitumor agent HMN-214, restores chemosensitivity to multidrug-resistant cells by targeting the transcription factor NF-Y. Cancer Res 2003; 63:6942-7.
197. Garland LL, Taylor C, Pilkington DL, Cohen JL, Von Hoff DD. A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors. Clin Cancer Res 2006; 12:5182-9.
198. Emmitte KA, Andrews CW, Badiang JG, et al. Discovery of thiophene inhibitors of polo-like kinase. Bioorg Med Chem Lett 2009; 19:1018-21.
199. Emmitte KA, Adjabeng GM, Andrews CW, et al. Design of potent thiophene inhibitors of polo-like kinase 1 with improved solubility and reduced protein binding. Bioorg Med Chem Lett 2009; 19: 1694-7.
200. Lenart P, Petronczki M, Steegmaier M, et al. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol 2007; 17:304-15.
201. Mross K, Frost A, Steinbild S, et al. Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol 2008; 26: 5511-7.
202. Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy:oncogene and non-oncogene addiction. Cell 2009; 136:823-37.
203. Liu X, Lei M, Erikson RL. Normal cells, but not cancer cells, survive severe Plkl depletion. Mol Cell Biol 2006; 26:2093-108.
204. Park JE, Li L, Park J, et al. Direct quantification of polo-like kinase 1 activity in cells and tissues using a highly sensitive and specific ELISA assay. Proc Natl Acad Sci U S A 2009; 106:1725-30.
205. Judge AD, Robbins M, Tavakoli I, et al. Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice. J Clin Invest 2009; 119:661-73.
206. Spankuch B, Steinhauser I, Wartlick H, Kurunci-Csacsko E, Strebhardt KI, Langer K. Downregulation of Plkl expression by receptor-mediated uptake of antisense oligonucleotide-loaded nanoparticles. Neoplasia 2008; 10:223-34.
207. Steinhauser IM, Langer K, Strebhardt KM, Spankuch B. Effect of trastuzumab-modified antisense oligonucleotide-loaded human serum albumin nanoparticles prepared by heat denaturation. Biomaterials 2008; 29:4022-8.
208. Steinhauser I, Langer K, Strebhardt K, Spankuch B. Uptake of plasmid-loaded nanoparticles in breast cancer cells and effect on Plkl expression. J Drug Target 2009; 17:627-37.
2. Smogorzewska A, de Lange T. Regulation of telomerase by telomeric proteins. Annu Rev Biochem 2004; 73:177-208.
3. Harrington L. Making the most of a little:dosage effects in eukaryotic telomere length maintenance. Chromosome Res 2005; 13:493-504.
4. Chong L, van Steensel B, Broccoli D, et al. A human telomeric protein. Science 1995; 270:1663-7.
5. Cerone MA, Autexier C, Londono-Vallejo JA, Bacchetti S. A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT. Oncogene 2005; 24:7893-901.
6. de Lange T. Shelterin:the protein complex that shapes and safeguards human telomeres. Genes Dev 2005; 19:2100-10.
7. O'Connor MS, Safari A, Xin H, Liu D, Songyang Z. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc Natl Acad Sci U S A 2006; 103:11874-9.
8. Liu D, O'Connor MS, Qin J, Songyang Z. Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem 2004; 279:51338-42.
9. Smogorzewska A, van Steensel B, Bianchi A, et al. Control of human telomere length by TRF1 and TRF2. Mol Cell Biol 2000; 20:1659-68.
10. Griffith JD, Comeau L, Rosenfield S, et al. Mammalian telomeres end in a large duplex loop. Cell 1999; 97:503-14.
11. van Steensel B, de Lange T. Control of telomere length by the human telomeric protein TRF1. Nature 1997; 385:740-3.
12. Sandell LL, Zakian VA. Loss of a yeast telomere:arrest, recovery, and chromosome loss. Cell 1993; 75:729-39.
13. Kirk KE, Harmon BP, Reichardt IK, Sedat JW, Blackburn EH. Block in anaphase chromosome separation caused by a telomerase template mutation. Science 1997; 275:1478-81.
14. Ahmad K, Golic KG. Telomere loss in somatic cells of Drosophila causes cell cycle arrest and apoptosis. Genetics 1999; 151:1041-51.
15. Kishi S, Zhou XZ, Ziv Y, et al. Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks. J Biol Chem 2001; 276:29282-91.
16. Iwano T, Tachibana M, Reth M, Shinkai Y. Importance of TRF1 for functional telomere structure. J Biol Chem 2004; 279:1442-8.
17. Nakamura M, Zhou XZ, Kishi S, Lu KP. Involvement of the telomeric protein Pin2/TRF1 in the regulation of the mitotic spindle. FEBS Lett 2002; 514:193-8.
18. Nakamura M, Zhou XZ, Kishi S, Kosugi I, Tsutsui Y, Lu KP. A specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle. Curr Biol 2001; 11:1512-6.
19. Zhu Q, Meng L, Hsu JK, Lin T, Teishima J, Tsai RY. GNL3L stabilizes the TRF1 complex and promotes mitotic transition. J Cell Biol 2009; 185:827-39.
20. Karlseder J, Kachatrian L, Takai H, et al. Targeted deletion reveals an essential function for the telomere length regulator Trf1. Mol Cell Biol 2003; 23:6533-41.
21. Chang W, Dynek JN, Smith S. TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes Dev 2003; 17:1328-33.
22. Cristofari G, Lingner J. Telomere length homeostasis requires that telomerase levels are limiting. Embo J 2006; 25:565-74.
23. Lee TH, Perrem K, Harper JW, Lu KP, Zhou XZ. The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance. J Biol Chem 2006; 281:759-68.
24. Seki A, Coppinger JA, Du H, Jang CY, Yates JR,3rd, Fang G. Plk1- and beta-TrCP-dependent degradation of Bora controls mitotic progression. J Cell Biol 2008; 181:65-78.
25. Kim MK, Kang MR, Nam HW, Bae YS, Kim YS, Chung IK. Regulation of telomeric repeat binding factor 1 binding to telomeres by casein kinase 2-mediated phosphorylation. J Biol Chem 2008; 283:14144-52.
26. Wu ZQ, Yang X, Weber G, Liu X. Plk1 phosphorylation of TRF1 is essential for its binding to telomeres. J Biol Chem 2008; 283:25503-13.
27. Smith S, de Lange T. Tankyrase promotes telomere elongation in human cells. Curr Biol 2000; 10: 1299-302.
28. Cook BD, Dynek JN, Chang W, Shostak G, Smith S. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol 2002; 22:332-42.
29. Smith S, Giriat I, Schmitt A, de Lange T. Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 1998; 282:1484-7.
30. Kim SH, Kaminker P, Campisi J. TIN2, a new regulator of telomere length in human cells. Nat Genet 1999; 23:405-12.
31. Ye JZ, de Lange T. TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat Genet 2004; 36:618-23.
32. Her YR, Chung IK. Ubiquitin Ligase RLIM Modulates Telomere Length Homeostasis through a Proteolysis of TRF1. J Biol Chem 2009; 284:8557-66.
33. Yu J, Lan J, Wang C, et al. PML3 interacts with TRF1 and is essential for ALT-associated PML bodies assembly in U2OS cells. Cancer Lett; 291:177-86.
1. Colgin L, Reddel R. Telomere biology:a new player in the end zone. Curr Biol 2004; 14:R901-2.
2. Smogorzewska A, de Lange T. Regulation of telomerase by telomeric proteins. Annu Rev Biochem 2004; 73:177-208.
3. de Lange T. Shelterin:the protein complex that shapes and safeguards human telomeres. Genes Dev 2005; 19:2100-10.
4. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet 2008; 42: 301-34.
5. De Boeck G, Forsyth RG, Praet M, Hogendoorn PC. Telomere-associated proteins:cross-talk between telomere maintenance and telomere-lengthening mechanisms. J Pathol 2009; 217:327-44.
6. Prime G, Markie D. The telomere repeat binding protein Trfl interacts with the spindle checkpoint protein Mad1 and Nek2 mitotic kinase. Cell Cycle 2005; 4:121-4.
7. Nakamura M, Zhou XZ, Kishi S, Kosugi I, Tsutsui Y, Lu KP. A specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle. Curr Biol 2001; 11:1512-6.
8. Zhou XZ, Perrem K, Lu KP. Role of Pin2/TRF1 in telomere maintenance and cell cycle control. J Cell Biochem 2003; 89:19-37.
9. Zhu Q, Meng L, Hsu JK, Lin T, Teishima J, Tsai RY. GNL3L stabilizes the TRF1 complex and promotes mitotic transition. J Cell Biol 2009; 185:827-39.
10. Zhou XZ, Lu KP. The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell 2001; 107:347-59.
11. Banik SS, Counter CM. Characterization of interactions between PinX1 and human telomerase subunits hTERT and hTR. J Biol Chem 2004; 279:51745-8.
12. Guglielmi B, Werner M. The yeast homolog of human PinX1 is involved in rRNA and small nucleolar RNA maturation, not in telomere elongation inhibition. J Biol Chem 2002; 277:35712-9.
13. Yoo JE, Oh BK, Park YN. Human PinX1 mediates TRF1 accumulation in nucleolus and enhances TRF1 binding to telomeres. J Mol Biol 2009; 388:928-40.
14. Yuan K, Li N, Jiang K, et al. PinX1 is a novel microtubule-binding protein essential for accurate chromosome segregation. J Biol Chem 2009; 284:23072-82.
15. Li N, Yuan K, Yan F, et al.PinX1 is recruited to the mitotic chromosome periphery by Nucleolin and facilitates chromosome congression. Biochem Biophys Res Commun 2009; 384:76-81.
16. van Vugt MA, Medema RH. Getting in and out of mitosis with Polo-like kinase-1. Oncogene 2005; 24:2844-59.
17. Petronczki M, Lenart P, Peters JM. Polo on the Rise-from Mitotic Entry to Cytokinesis with Plkl. Dev Cell 2008; 14:646-59.
18. Lowery DM, Lim D, Yaffe MB. Structure and function of Polo-like kinases. Oncogene 2005; 24: 248-59.
19. Dai W, Wang X. Grabbing Plkl by the PBD. Mol Cell 2006; 24:489-90.
20. Wu ZQ, Yang X, Weber G, Liu X. Plkl phosphorylation of TRF1 is essential for its binding to telomeres. J Biol Chem 2008; 283:25503-13.
21. Nishiyama A, Muraki K, Saito M, Ohsumi K, Kishimoto T, Ishikawa F. Cell-cycle-dependent Xenopus TRF1 recruitment to telomere chromatin regulated by Polo-like kinase. Embo J 2006; 25: 575-84.
22. Mamely I, van Vugt MA, Smits VA, et al. Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery. Curr Biol 2006; 16:1950-5.
23. Moshe Y, Boulaire J, Pagano M, Hershko A. Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proc Natl Acad Sci U S A 2004; 101:7937-42.
1. Blasco MA, Lee HW, Hande MP, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 1997; 91:25-34.
2. Smogorzewska A, de Lange T. Regulation of telomerase by telomeric proteins. Annu Rev Biochem 2004; 73:177-208.
3. Harrington L. Making the most of a little:dosage effects in eukaryotic telomere length maintenance. Chromosome Res 2005; 13:493-504.
4. Chong L, van Steensel B, Broccoli D, et al. A human telomeric protein. Science 1995; 270:1663-7.
5. Cerone MA, Autexier C, Londono-Vallejo JA, Bacchetti S. A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT. Oncogene 2005; 24:7893-901.
6. de Lange T. Shelterin:the protein complex that shapes and safeguards human telomeres. Genes Dev 2005; 19:2100-10.
7. O'Connor MS, Safari A, Xin H, Liu D, Songyang Z. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc Natl Acad Sci U S A 2006; 103:11874-9.
8. Liu D, O'Connor MS, Qin J, Songyang Z. Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem 2004; 279:51338-42.
9. Smogorzewska A, van Steensel B, Bianchi A, et al. Control of human telomere length by TRF1 and TRF2. Mol Cell Biol 2000; 20:1659-68.
10. Griffith JD, Comeau L, Rosenfield S, et al. Mammalian telomeres end in a large duplex loop. Cell 1999; 97:503-14.
11. van Steensel B, de Lange T. Control of telomere length by the human telomeric protein TRF1. Nature 1997; 385:740-3.
12. Sandell LL, Zakian VA. Loss of a yeast telomere:arrest, recovery, and chromosome loss. Cell 1993; 75:729-39.
13. Kirk KE, Harmon BP, Reichardt IK, Sedat JW, Blackburn EH. Block in anaphase chromosome separation caused by a telomerase template mutation. Science 1997; 275:1478-81.
14. Ahmad K, Golic KG. Telomere loss in somatic cells of Drosophila causes cell cycle arrest and apoptosis. Genetics 1999; 151:1041-51.
15. Kishi S, Zhou XZ, Ziv Y, et al. Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks. J Biol Chem 2001; 276:29282-91.
16. Iwano T, Tachibana M, Reth M, Shinkai Y. Importance of TRF1 for functional telomere structure. J Biol Chem 2004; 279:1442-8.
17. Nakamura M, Zhou XZ, Kishi S, Lu KP. Involvement of the telomeric protein Pin2/TRF1 in the regulation of the mitotic spindle. FEBS Lett 2002; 514:193-8.
18. Nakamura M, Zhou XZ, Kishi S, Kosugi I, Tsutsui Y, Lu KP. A specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle. Curr Biol 2001; 11:1512-6.
19. Zhu Q, Meng L, Hsu JK, Lin T, Teishima J, Tsai RY. GNL3L stabilizes the TRF1 complex and promotes mitotic transition. J Cell Biol 2009; 185:827-39.
20. Karlseder J, Kachatrian L, Takai H, et al. Targeted deletion reveals an essential function for the telomere length regulator Trf1. Mol Cell Biol 2003; 23:6533-41.
21. Chang W, Dynek JN, Smith S. TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes Dev 2003; 17:1328-33.
22. Cristofari G, Lingner J. Telomere length homeostasis requires that telomerase levels are limiting. Embo J 2006; 25:565-74.
23. Lee TH, Perrem K, Harper JW, Lu KP, Zhou XZ. The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance. J Biol Chem 2006; 281: 759-68.
24. Seki A, Coppinger JA, Du H, Jang CY, Yates JR,3rd, Fang G. Plkl- and beta-TrCP-dependent degradation of Bora controls mitotic progression. J Cell Biol 2008; 181:65-78.
25. Kim MK, Kang MR, Nam HW, Bae YS, Kim YS, Chung IK. Regulation of telomeric repeat binding factor 1 binding to telomeres by casein kinase 2-mediated phosphorylation. J Biol Chem 2008; 283: 14144-52.
26. Wu ZQ, Yang X, Weber G, Liu X. Plkl phosphorylation of TRF1 is essential for its binding to telomeres. J Biol Chem 2008; 283:25503-13.
27. Smith S, de Lange T. Tankyrase promotes telomere elongation in human cells. Curr Biol 2000; 10: 1299-302.
28. Cook BD, Dynek JN, Chang W, Shostak G, Smith S. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol 2002; 22:332-42.
29. Smith S, Giriat I, Schmitt A, de Lange T. Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 1998; 282:1484-7.
30. Kim SH, Kaminker P, Campisi J. TIN2, a new regulator of telomere length in human cells. Nat Genet 1999; 23:405-12.
31. Ye JZ, de Lange T. TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat Genet 2004; 36:618-23.
32. Her YR, Chung IK. Ubiquitin Ligase RLIM Modulates Telomere Length Homeostasis through a Proteolysis of TRF1. J Biol Chem 2009; 284:8557-66.
33. Yu J, Lan J, Wang C, et al. PML3 interacts with TRF1 and is essential for ALT-associated PML bodies assembly in U2OS cells. Cancer Lett; 291:177-86.
34. Colgin L, Reddel R. Telomere biology:a new player in the end zone. Curr Biol 2004; 14:R901-2.
35. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet 2008; 42: 301-34.
36. De Boeck G, Forsyth RG, Praet M, Hogendoorn PC. Telomere-associated proteins:cross-talk between telomere maintenance and telomere-lengthening mechanisms. J Pathol 2009; 217:327-44.
37. Prime G, Markie D. The telomere repeat binding protein Trfl interacts with the spindle checkpoint protein Mad1 and Nek2 mitotic kinase. Cell Cycle 2005; 4:121-4.
38. Zhou XZ, Perrem K, Lu KP. Role of Pin2/TRF1 in telomere maintenance and cell cycle control. J Cell Biochem 2003; 89:19-37.
39. Zhou XZ, Lu KP. The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell 2001; 107:347-59.
40. Banik SS, Counter CM. Characterization of interactions between PinX1 and human telomerase subunits hTERT and hTR. J Biol Chem 2004; 279:51745-8.
41. Guglielmi B, Werner M. The yeast homolog of human PinX1 is involved in rRNA and small nucleolar RNA maturation, not in telomere elongation inhibition. J Biol Chem 2002; 277:35712-9.
42. Yoo JE, Oh BK, Park YN. Human PinX1 mediates TRF1 accumulation in nucleolus and enhances TRF1 binding to telomeres. J Mol Biol 2009; 388:928-40.
43. Yuan K, Li N, Jiang K, et al. PinX1 is a novel microtubule-binding protein essential for accurate chromosome segregation. J Biol Chem 2009; 284:23072-82.
44. Li N, Yuan K, Yan F, et al. PinX1 is recruited to the mitotic chromosome periphery by Nucleolin and facilitates chromosome congression. Biochem Biophys Res Commun 2009; 384:76-81.
45. van Vugt MA, Medema RH. Getting in and out of mitosis with Polo-like kinase-1. Oncogene 2005; 24:2844-59.
46. Petronczki M, Lenart P, Peters JM. Polo on the Rise-from Mitotic Entry to Cytokinesis with Plkl. Dev Cell 2008; 14:646-59.
47. Lowery DM, Lim D, Yaffe MB. Structure and function of Polo-like kinases. Oncogene 2005; 24: 248-59.
48. Dai W, Wang X. Grabbing Plkl by the PBD. Mol Cell 2006; 24:489-90.
49. Nishiyama A, Muraki K, Saito M, Ohsumi K, Kishimoto T, Ishikawa F. Cell-cycle-dependent Xenopus TRF1 recruitment to telomere chromatin regulated by Polo-like kinase. Embo J 2006; 25: 575-84.
50. Mamely I, van Vugt MA, Smits VA, et al. Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery. Curr Biol 2006; 16:1950-5.
51. Moshe Y, Boulaire J, Pagano M, Hershko A. Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proc Natl Acad Sci U S A 2004; 101:7937-42.
52. Sunkel CE, Glover DM. polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J Cell Sci 1988; 89 (Pt 1):25-38.
53. Llamazares S, Moreira A, Tavares A, et al. polo encodes a protein kinase homolog required for mitosis in Drosophila. Genes Dev 1991; 5:2153-65.
54. Glover DM, Hagan IM, Tavares AA. Polo-like kinases:a team that plays throughout mitosis. Genes Dev 1998; 12:3777-87.
55. Barr FA, Sillje HH, Nigg EA. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol 2004; 5:429-40.
56. Andrysik Z, Bernstein WZ, Deng L, et al. The novel mouse Polo-like kinase 5 responds to DNA damage and localizes in the nucleolus. Nucleic Acids Res 2010; 38:2931-43.
57. Clay FJ, McEwen SJ, Bertoncello I, Wilks AF, Dunn AR. Identification and cloning of a protein kinase-encoding mouse gene, Plk, related to the polo gene of Drosophila. Proc Natl Acad Sci U S A 1993; 90:4882-6.
58. van de Weerdt BC, Medema RH. Polo-like kinases:a team in control of the division. Cell Cycle 2006; 5:853-64.
59. Takaki T, Trenz K, Costanzo V, Petronczki M. Polo-like kinase 1 reaches beyond mitosis--cytokinesis, DNA damage response, and development. Curr Opin Cell Biol 2008; 20: 650-60.
60. Archambault V, Glover DM. Polo-like kinases:conservation and divergence in their functions and regulation. Nat Rev Mol Cell Biol 2009; 10:265-75.
61. Cogswell JP, Brown CE, Bisi JE, Neill SD. Dominant-negative polo-like kinase 1 induces mitotic catastrophe independent of cdc25C function. Cell Growth Differ 2000; 11:615-23.
62. Spankuch-Schmitt B, Wolf G, Solbach C, et al. Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells. Oncogene 2002; 21: 3162-71.
63. Spankuch-Schmitt B, Bereiter-Hahn J, Kaufmann M, Strebhardt K. Effect of RNA silencing of polo-like kinase-1 (PLK1) on apoptosis and spindle formation in human cancer cells. J Natl Cancer Inst 2002;94:1863-77.
64. Liu X, Erikson RL. Activation of Cdc2/cyclin B and inhibition of centrosome amplification in cells depleted of Plk 1 by siRNA. Proc Natl Acad Sci U S A 2002; 99:8672-6.
65. Strebhardt K, Ullrich A. Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer 2006; 6: 321-30.
66. Strebhardt K, Ullrich A. Paul Ehrlich's magic bullet concept:100 years of progress. Nat Rev Cancer 2008; 8:473-80.
67. Schoffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist 2009; 14:559-70.
68. McInnes C, Mezna M, Fischer PM. Progress in the discovery of polo-like kinase inhibitors. Curr Top Med Chem 2005; 5:181-97.
69. Xie S, Wang Q, Wu H, et al. Reactive oxygen species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like kinase-3. J Biol Chem 2001; 276:36194-9.
70. Xie S, Wu H, Wang Q, et al. Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway. J Biol Chem 2001; 276:43305-12.
71. Shimizu-Yoshida Y, Sugiyama K, Rogounovitch T, et al. Radiation-inducible hSNK gene is transcriptionally regulated by p53 binding homology element in human thyroid cells. Biochem Biophys Res Commun 2001; 289:491-8.
72. Holtrich U, Wolf G, Brauninger A, et al. Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors. Proc Natl Acad Sci U S A 1994; 91:1736-40.
73. Lu LY, Wood JL, Minter-Dykhouse K, et al. Polo-like kinase 1 is essential for early embryonic development and tumor suppression. Mol Cell Biol 2008; 28:6870-6.
74. Kitada K, Johnson AL, Johnston LH, Sugino A. A multicopy suppressor gene of the Saccharomyces cerevisiae G1 cell cycle mutant gene dbf4 encodes a protein kinase and is identified as CDC5. Mol Cell Biol 1993; 13:4445-57.
75. Ohkura H, Hagan IM, Glover DM. The conserved Schizosaccharomyces pombe kinase plol, required to form a bipolar spindle, the actin ring, and septum, can drive septum formation in G1 and G2 cells. Genes Dev 1995; 9:1059-73.
76. Lowery DM, Clauser KR, Hjerrild M, et al. Proteomic screen defines the Polo-box domain interactome and identifies Rock2 as a Plk1 substrate. EMBO J 2007; 26:2262-73.
77. Lee KS, Grenfell TZ, Yarm FR, Erikson RL. Mutation of the polo-box disrupts localization and mitotic functions of the mammalian polo kinase Plk. Proc Natl Acad Sci U S A 1998; 95:9301-6.
78. van de Weerdt BC, Littler DR, Klompmaker R, et al. Polo-box domains confer target specificity to the Polo-like kinase family. Biochim Biophys Acta 2008; 1783:1015-22.
79. Seong YS, Kamijo K, Lee JS, et al. A spindle checkpoint arrest and a cytokinesis failure by the dominant-negative polo-box domain of Plkl in U-2 OS cells. J Biol Chem 2002; 277:32282-93.
80. Song S, Grenfell TZ, Garfield S, Erikson RL, Lee KS. Essential function of the polo box of Cdc5 in subcellular localization and induction of cytokinetic structures. Mol Cell Biol 2000; 20:286-98.
81. Neef R, Preisinger C, Sutcliffe J, et al. Phosphorylation of mitotic kinesin-like protein 2 by polo-like kinase 1 is required for cytokinesis. J Cell Biol 2003; 162:863-75.
82. Kang YH, Park JE, Yu LR, et al. Self-regulated Plkl recruitment to kinetochores by the Plk1-PBIP1 interaction is critical for proper chromosome segregation. Mol Cell 2006; 24:409-22.
83. Neef R, Gruneberg U, Kopajtich R, et al. Choice of Plkl docking partners during mitosis and cytokinesis is controlled by the activation state of Cdkl. Nat Cell Biol 2007; 9:436-44.
84. Jang YJ, Lin CY, Ma S, Erikson RL. Functional studies on the role of the C-terminal domain of mammalian polo-like kinase. Proc Natl Acad Sci U S A 2002; 99:1984-9.
85. Elia AE, Rellos P, Haire LF, et al. The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain. Cell 2003; 115:83-95.
86. Golsteyn RM, Mundt KE, Fry AM, Nigg EA. Cell cycle regulation of the activity and subcellular localization of Plk1, a human protein kinase implicated in mitotic spindle function. J Cell Biol 1995; 129:1617-28.
87 Jang YJ, Ma S, Terada Y, Erikson RL. Phosphorylation of threonine 210 and the role of serine 137 in the regulation of mammalian polo-like kinase. J Biol Chem 2002; 277:44115-20.
88. Daub H, Olsen JV, Bairlein M, et al. Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell 2008; 31:438-48.
89. Qian YW, Erikson E, Maller JL. Purification and cloning of a protein kinase that phosphorylates and activates the polo-like kinase Plxl. Science 1998; 282:1701-4.
90. Kelm O, Wind M, Lehmann WD, Nigg EA. Cell cycle-regulated phosphorylation of the Xenopus polo-like kinase Plxl. J Biol Chem 2002; 277:25247-56.
91. Ellinger-Ziegelbauer H, Karasuyama H, Yamada E, Tsujikawa K, Todokoro K, Nishida E. Ste20-like kinase (SLK), a regulatory kinase for polo-like kinase (Plk) during the G2/M transition in somatic cells. Genes Cells 2000; 5:491-8.
92. Seki A, Coppinger JA, Jang CY, Yates JR, Fang G. Bora and the kinase Aurora a cooperatively activate the kinase Plkl and control mitotic entry. Science 2008; 320:1655-8.
93. Macurek L, Lindqvist A, Lim D, et al. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature 2008; 455:119-23.
94. Chan EH, Santamaria A, Sillje HH, Nigg EA. Plk1 regulates mitotic Aurora A function through betaTrCP-dependent degradation of hBora. Chromosoma 2008; 117:457-69.
95. Laoukili J, Kooistra MR, Bras A, et al. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat Cell Biol 2005; 7:126-36.
96. Major ML, Lepe R, Costa RH. Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. Mol Cell Biol 2004; 24:2649-61.
97. Fu Z, Malureanu L, Huang J, et al. Plkl-dependent phosphorylation of FoxMl regulates a transcriptional programme required for mitotic progression. Nat Cell Biol 2008; 10:1076-82.
98. Wang IC, Chen YJ, Hughes D, et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cksl) ubiquitin ligase. Mol Cell Biol 2005; 25:10875-94.
99. Ando K, Ozaki T, Yamamoto H, et al. Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation. J Biol Chem 2004; 279:25549-61.
100. Whibley C, Pharoah PD, Hollstein M. p53 polymorphisms:cancer implications. Nat Rev Cancer 2009; 9:95-107.
101. Vazquez A, Bond EE, Levine AJ, Bond GL. The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov 2008; 7:979-87.
102. Liu X, Erikson RL. Polo-like kinase (Plk) 1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci U S A 2003; 100:5789-94.
103. Yang X, Li H, Zhou Z, et al. Plkl-mediated phosphorylation of Topors regulates p53 stability. J Biol Chem 2009; 284:18588-92.
104. Weger S, Hammer E, Heilbronn R. Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo. FEBS Lett 2005; 579:5007-12.
105. Rajendra R, Malegaonkar D, Pungaliya P, et al. Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J Biol Chem 2004; 279:36440-4.
106. Koida N, Ozaki T, Yamamoto H, et al. Inhibitory role of Plkl in the regulation of p73-dependent apoptosis through physical interaction and phosphorylation. J Biol Chem 2008; 283:8555-63.
107. Soond SM, Barry SP, Melino G, Knight RA, Latchman DS, Stephanou A. p73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. Cell Cycle 2008; 7:1214-23.
108. Sur S, Pagliarini R, Bunz F, et al. A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc Natl Acad Sci U S A 2009; 106:3964-9.
109. zur Hausen H. Papillomaviruses and cancer:from basic studies to clinical application. Nat Rev Cancer 2002; 2:342-50.
110.Patel D, Incassati A, Wang N, McCance DJ. Human papillomavirus type 16 E6 and E7 cause polyploidy in human keratinocytes and up-regulation of G2-M-phase proteins. Cancer Res 2004; 64: 1299-306.
111.Incassati A, Patel D, McCance DJ. Induction of tetraploidy through loss of p53 and upregulation of Plkl by human papillomavirus type-16 E6. Oncogene 2006; 25:2444-51.
112.Meraldi P, Honda R, Nigg EA. Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53-/- cells. EMBO J 2002; 21:483-92.
113.Lin HR, Ting NS, Qin J, Lee WH. M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex. J Biol Chem 2003; 278: 35979-87.
114.Lee M, Daniels MJ, Venkitaraman AR. Phosphorylation of BRCA2 by the Polo-like kinase Plkl is regulated by DNA damage and mitotic progression. Oncogene 2004; 23:865-72.
115.Tsvetkov L, Xu X, Li J, Stern DF. Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody. J Biol Chem 2003; 278:8468-75.
116.Smits VA, Klompmaker R, Arnaud L, Rijksen G, Nigg EA, Medema RH. Polo-like kinase-1 is a target of the DNA damage checkpoint. Nat Cell Biol 2000; 2:672-6.
117.Syljuasen RG, Jensen S, Bartek J, Lukas J. Adaptation to the ionizing radiation-induced G2 checkpoint occurs in human cells and depends on checkpoint kinase 1 and Polo-like kinase 1 kinases. Cancer Res 2006; 66:10253-7.
118.Yamaguchi T, Goto H, Yokoyama T, et al. Phosphorylation by Cdkl induces Plkl-mediated vimentin phosphorylation during mitosis. J Cell Biol 2005; 171:431-6.
119.Liu L, Zhang M, Zou P. Expression of PLK1 and survivin in diffuse large B-cell lymphoma. Leuk Lymphoma 2007; 48:2179-83.
120. Yamamoto Y, Matsuyama H, Kawauchi S, et al. Overexpression of polo-like kinase 1 (PLK1) and chromosomal instability in bladder cancer. Oncology 2006; 70:231-7.
121. Liu L, Zhang M, Zou P. Polo-like kinase 1 as a new target for non-Hodgkin's lymphoma treatment. Oncology 2008; 74:96-103.
122. Kanaji S, Saito H, Tsujitani S, et al. Expression of polo-like kinase 1 (PLK1) protein predicts the survival of patients with gastric carcinoma. Oncology 2006; 70:126-33.
123. Jang YJ, Kim YS, Kim WH. Oncogenic effect of Polo-like kinase 1 expression in human gastric carcinomas. Int J Oncol 2006; 29:589-94.
124. Simmons DL, Neel BG, Stevens R, Evett G, Erikson RL. Identification of an early-growth-response gene encoding a novel putative protein kinase. Mol Cell Biol 1992; 12:4164-9.
125. Anger M, Kues WA, Klima J, et al. Cell cycle dependent expression of Plkl in synchronized porcine fetal fibroblasts. Mol Reprod Dev 2003; 65:245-53.
126. Warnke S, Kemmler S, Hames RS, et al. Polo-like kinase-2 is required for centriole duplication in mammalian cells. Curr Biol 2004; 14:1200-7.
127. Cizmecioglu O, Warnke S, Arnold M, Duensing S, Hoffmann I. Plk2 regulated centriole duplication is dependent on its localization to the centrioles and a functional polo-box domain. Cell Cycle 2008; 7:3548-55.
128. Ma S, Charron J, Erikson RL. Role of Plk2 (Snk) in mouse development and cell proliferation. Mol Cell Biol 2003; 23:6936-43.
129. Ma S, Liu MA, Yuan YL, Erikson RL. The serum-inducible protein kinase Snk is a G1 phase polo-like kinase that is inhibited by the calcium- and integrin-binding protein CIB. Mol Cancer Res 2003; 1:376-84.
130. Kauselmann G, Weiler M, Wulff P, et al. The polo-like protein kinases Fnk and Snk associate with a Ca(2+)- and integrin-binding protein and are regulated dynamically with synaptic plasticity. EMBO J 1999; 18:5528-39.
131. Burns TF, Fei P, Scata KA, Dicker DT, El-Deiry WS. Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (taxol)-exposed cells. Mol Cell Biol 2003; 23: 5556-71.
132. Tovar C, Rosinski J, Filipovic Z, et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer:implications for therapy. Proc Natl Acad Sci U S A 2006; 103:1888-93.
133. Syed N, Smith P, Sullivan A, et al. Transcriptional silencing of Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies. Blood 2006; 107:250-6.
134. Donohue PJ, Alberts GF, Guo Y, Winkles JA. Identification by targeted differential display of an immediate early gene encoding a putative serine/threonine kinase. J Biol Chem 1995; 270:10351-7.
135. Holtrich U, Wolf G, Yuan J, et al. Adhesion induced expression of the serine/threonine kinase Fnk in human macrophages. Oncogene 2000; 19:4832-9.
136. Ouyang B, Pan H, Lu L, et al. Human Prk is a conserved protein serine/threonine kinase involved in regulating M phase functions. J Biol Chem 1997; 272:28646-51.
137. Chase D, Feng Y, Hanshew B, Winkles JA, Longo DL, Ferris DK. Expression and phosphorylation of fibroblast-growth-factor-inducible kinase (Fnk) during cell-cycle progression. Biochem J 1998; 333 (Pt 3):655-60.
138. Bahassi el M, Conn CW, Myer DL, et al. Mammalian Polo-like kinase 3 (Plk3) is a multifunctional protein involved in stress response pathways. Oncogene 2002; 21:6633-40.
139. Zimmerman WC, Erikson RL. Polo-like kinase 3 is required for entry into S phase. Proc Natl Acad Sci U S A 2007;104:1847-52.
140. Wang Q, Xie S, Chen J, et al. Cell cycle arrest and apoptosis induced by human Polo-like kinase 3 is mediated through perturbation of microtubule integrity. Mol Cell Biol 2002; 22:3450-9.
141. Jiang N, Wang X, Jhanwar-Uniyal M, Darzynkiewicz Z, Dai W. Polo box domain of Plk3 functions as a centrosome localization signal, overexpression of which causes mitotic arrest, cytokinesis defects, and apoptosis. J Biol Chem 2006; 281:10577-82.
142. Yang F, Camp DG,2nd, Gritsenko MA, et al. Identification of a novel mitotic phosphorylation motif associated with protein localization to the mitotic apparatus. J Cell Sci 2007; 120:4060-70.
143. Ruan Q, Wang Q, Xie S, et al. Polo-like kinase 3 is Golgi localized and involved in regulating Golgi fragmentation during the cell cycle. Exp Cell Res 2004; 294:51-9.
144. Lopez-Sanchez I, Sanz-Garcia M, Lazo PA. Plk3 interacts with and specifically phosphorylates VRK1 in Ser342, a downstream target in a pathway that induces Golgi fragmentation. Mol Cell Biol 2009; 29:1189-201.
145. Sutterlin C, Hsu P, Mallabiabarrena A, Malhotra V. Fragmentation and dispersal of the pericentriolar Golgi complex is required for entry into mitosis in mammalian cells. Cell 2002; 109: 359-69.
146. Li B, Ouyang B, Pan H, et al. Prk, a cytokine-inducible human protein serine/threonine kinase whose expression appears to be down-regulated in lung carcinomas. J Biol Chem 1996; 271: 19402-8.
147. Conn CW, Hennigan RF, Dai W, Sanchez Y, Stambrook PJ. Incomplete cytokinesis and induction of apoptosis by overexpression of the mammalian polo-like kinase, Plk3. Cancer Res 2000; 60: 6826-31.
148. Zhou T, Chou JW, Simpson DA, et al. Profiles of global gene expression in ionizing-radiation-damaged human diploid fibroblasts reveal synchronization behind the G1 checkpoint in a G0-like state of quiescence. Environ Health Perspect 2006; 114:553-9.
149. Staib F, Robles Al, Varticovski L, et al. The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. Cancer Res 2005; 65:10255-64.
150. Dai W, Li Y, Ouyang B, et al. PRK, a cell cycle gene localized to 8p21, is downregulated in head and neck cancer. Genes Chromosomes Cancer 2000; 27:332-6.
151. Yang Y, Bai J, Shen R, et al. Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditions. Cancer Res 2008; 68: 4077-85.
152. Weichert W, Kristiansen G, Winzer KJ, et al. Polo-like kinase isoforms in breast cancer:expression patterns and prognostic implications. Virchows Arch 2005; 446:442-50.
153. Weichert W, Denkert C, Schmidt M, et al. Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma. Br J Cancer 2004; 90:815-21.
154. Fode C, Motro B, Yousefi S, Heffernan M, Dennis JW. Sak, a murine protein-serine/threonine kinase that is related to the Drosophila polo kinase and involved in cell proliferation. Proc Natl Acad SciUSA1994; 91:6388-92.
155. Fode C, Binkert C, Dennis JW. Constitutive expression of murine Sak-a suppresses cell growth and induces multinucleation. Mol Cell Biol 1996; 16:4665-72.
156. Hudson JW, Kozarova A, Cheung P, et al. Late mitotic failure in mice lacking Sak, a polo-like kinase. Curr Biol 2001; 11:441-6.
157. Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA. The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol 2005; 7:1140-6.
158. Bettencourt-Dias M, Rodrigues-Martins A, Carpenter L, et al. SAK/PLK4 is required for centriole duplication and flagella development. Curr Biol 2005; 15:2199-207.
159. Li J, Tan M, Li L, Pamarthy D, Lawrence TS, Sun Y. SAK, a new polo-like kinase, is transcriptionally repressed by p53 and induces apoptosis upon RNAi silencing. Neoplasia 2005; 7: 312-23.
160. Deloukas P, Schuler GD, Gyapay G, et al. A physical map of 30,000 human genes. Science 1998; 282:744-6.
161. Hammond C, Jeffers L, Carr BI, Simon D. Multiple genetic alterations,4q28, a new suppressor region, and potential gender differences in human hepatocellular carcinoma. Hepatology 1999; 29: 1479-85.
162. Macmillan JC, Hudson JW, Bull S, Dennis JW, Swallow CJ. Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer. Ann Surg Oncol 2001; 8:729-40.
163. Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 2004; 4:927-36.
164. Perez de Castro I, de Carcer G, Montoya G, Malumbres M. Emerging cancer therapeutic opportunities by inhibiting mitotic kinases. Curr Opin Pharmacol 2008; 8:375-83.
165. Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 2009; 8:547-66.
166. Lane HA, Nigg EA. Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plkl) in the functional maturation of mitotic centrosomes. J Cell Biol 1996; 135:1701-13.
167. Yuan J, Kramer A, Eckerdt F, Kaufmann M, Strebhardt K. Efficient internalization of the polo-box of polo-like kinase 1 fused to an Antennapedia peptide results in inhibition of cancer cell proliferation. Cancer Res 2002; 62:4186-90.
168. Spankuch B, Matthess Y, Knecht R, Zimmer B, Kaufmann M, Strebhardt K. Cancer inhibition in nude mice after systemic application of U6 promoter-driven short hairpin RNAs against PLK1. J Natl Cancer Inst 2004; 96:862-72.
169. Kappel S, Matthess Y, Zimmer B, Kaufmann M, Strebhardt K. Tumor inhibition by genomically integrated inducible RNAi-cassettes. Nucleic Acids Res 2006; 34:4527-36.
170. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298:1912-34.
171. Goldstein DM, Gray NS, Zarrinkar PP. High-throughput kinase profiling as a platform for drug discovery. Nat Rev Drug Discov 2008; 7:391-7.
172. Johnson EF, Stewart KD, Woods KW, Giranda VL, Luo Y. Pharmacological and functional comparison of the polo-like kinase family:insight into inhibitor and substrate specificity. Biochemistry 2007; 46:9551-63.
173. Kothe M, Kohls D, Low S, et al. Structure of the catalytic domain of human polo-like kinase 1. Biochemistry 2007; 46:5960-71.
174. Steegmaier M, Hoffmann M, Baum A, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol 2007; 17:316-22.
175. Wang HY, Cao ZX, Li LL, et al. Pharmacophore modeling and virtual screening for designing potential PLK1 inhibitors. Bioorg Med Chem Lett 2008; 18:4972-7.
176. McInnes C, Mazumdar A, Mezna M, et al. Inhibitors of Polo-like kinase reveal roles in spindle-pole maintenance. Nat Chem Biol 2006; 2:608-17.
177. Peters U, Cherian J, Kim JH, Kwok BH, Kapoor TM. Probing cell-division phenotype space and Polo-like kinase function using small molecules. Nat Chem Biol 2006; 2:618-26.
178. Santamaria A, Neef R, Eberspacher U, et al. Use of the novel Plkl inhibitor ZK-thiazolidinone to elucidate functions of Plkl in early and late stages of mitosis. Mol Biol Cell 2007; 18:4024-36.
179. Lansing TJ, McConnell RT, Duckett DR, et al. In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1. Mol Cancer Ther 2007; 6:450-9.
180. Baumann C, Korner R, Hofmann K, Nigg EA. PICH, a centromere-associated SNF2 family ATPase, is regulated by Plkl and required for the spindle checkpoint. Cell 2007; 128:101-14.
181. Sato Y, Onozaki Y, Sugimoto T, et al. Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors. Bioorg Med Chem Lett 2009; 19:4673-8.
182. Uckun FM, Dibirdik I, Qazi S, et al. Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK). Bioorg Med Chem 2007; 15:800-14.
183. Uckun FM. Chemosensitizing anti-cancer activity of LFM-A13, a leflunomide metabolite analog targeting polo-like kinases. Cell Cycle 2007; 6:3021-6.
184. Reindl W, Yuan J, Kramer A, Strebhardt K, Berg T. Inhibition of polo-like kinase 1 by blocking polo-box domain-dependent protein-protein interactions. Chem Biol 2008; 15:459-66.
185. Reindl W, Strebhardt K, Berg T. A high-throughput assay based on fluorescence polarization for inhibitors of the polo-box domain of polo-like kinase 1. Anal Biochem 2008; 383:205-9.
186. Hanisch A, Wehner A, Nigg EA, Sillje HH. Different Plkl functions show distinct dependencies on Polo-Box domain-mediated targeting. Mol Biol Cell 2006; 17:448-59.
187. Gali-Muhtasib H, Roessner A, Schneider-Stock R. Thymoquinone:a promising anti-cancer drug from natural sources. Int J Biochem Cell Biol 2006; 38:1249-53.
188. Kaseb AO, Chinnakannu K, Chen D, et al. Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer. Cancer Res 2007; 67:7782-8.
189. Watanabe N, Sekine T, Takagi M, et al. Deficiency in chromosome congression by the inhibition of Plkl polo box domain-dependent recognition. J Biol Chem 2009; 284:2344-53.
190. Abou-Karam M, Shier WT. Inhibition of oncogene product enzyme activity as an approach to cancer chemoprevention. Tyrosine-specific protein kinase inhibition by purpurogallin from Quercus sp. nutgall. Phytother Res 1999; 13:337-40.
191. Farnet CM, Wang B, Hansen M, et al. Human immunodeficiency virus type 1 cDNA integration: new aromatic hydroxylated inhibitors and studies of the inhibition mechanism. Antimicrob Agents Chemother 1998; 42:2245-53.
192. Jackson JR, Patrick DR, Dar MM, Huang PS. Targeted anti-mitotic therapies:can we improve on tubulin agents? Nat Rev Cancer 2007; 7:107-17.
193. Gumireddy K, Reddy MV, Cosenza SC, et al. ON01910, a non-ATP-competitive small molecule inhibitor of Plkl, is a potent anticancer agent. Cancer Cell 2005; 7:275-86.
194. Jimeno A, Li J, Messersmith WA, et al. Phase I study of ON 01910.Na, a novel modulator of the Polo-like kinase 1 pathway, in adult patients with solid tumors. J Clin Oncol 2008; 26:5504-10.
195. Jimeno A, Chan A, Cusatis G, et al. Evaluation of the novel mitotic modulator ON 01910.Na in pancreatic cancer and preclinical development of an ex vivo predictive assay. Oncogene 2009; 28: 610-8.
196. Tanaka H, Ohshima N, Ikenoya M, Komori K, Katoh F, Hidaka H. HMN-176, an active metabolite of the synthetic antitumor agent HMN-214, restores chemosensitivity to multidrug-resistant cells by targeting the transcription factor NF-Y. Cancer Res 2003; 63:6942-7.
197. Garland LL, Taylor C, Pilkington DL, Cohen JL, Von Hoff DD. A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors. Clin Cancer Res 2006; 12:5182-9.
198. Emmitte KA, Andrews CW, Badiang JG, et al. Discovery of thiophene inhibitors of polo-like kinase. Bioorg Med Chem Lett 2009; 19:1018-21.
199. Emmitte KA, Adjabeng GM, Andrews CW, et al. Design of potent thiophene inhibitors of polo-like kinase 1 with improved solubility and reduced protein binding. Bioorg Med Chem Lett 2009; 19: 1694-7.
200. Lenart P, Petronczki M, Steegmaier M, et al. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol 2007; 17:304-15.
201. Mross K, Frost A, Steinbild S, et al. Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol 2008; 26: 5511-7.
202. Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy:oncogene and non-oncogene addiction. Cell 2009; 136:823-37.
203. Liu X, Lei M, Erikson RL. Normal cells, but not cancer cells, survive severe Plkl depletion. Mol Cell Biol 2006; 26:2093-108.
204. Park JE, Li L, Park J, et al. Direct quantification of polo-like kinase 1 activity in cells and tissues using a highly sensitive and specific ELISA assay. Proc Natl Acad Sci U S A 2009; 106:1725-30.
205. Judge AD, Robbins M, Tavakoli I, et al. Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice. J Clin Invest 2009; 119:661-73.
206. Spankuch B, Steinhauser I, Wartlick H, Kurunci-Csacsko E, Strebhardt KI, Langer K. Downregulation of Plkl expression by receptor-mediated uptake of antisense oligonucleotide-loaded nanoparticles. Neoplasia 2008; 10:223-34.
207. Steinhauser IM, Langer K, Strebhardt KM, Spankuch B. Effect of trastuzumab-modified antisense oligonucleotide-loaded human serum albumin nanoparticles prepared by heat denaturation. Biomaterials 2008; 29:4022-8.
208. Steinhauser I, Langer K, Strebhardt K, Spankuch B. Uptake of plasmid-loaded nanoparticles in breast cancer cells and effect on Plkl expression. J Drug Target 2009; 17:627-37.