微囊藻毒素LR刺激HEK293细胞产生的PP2A调节机制及其对细胞凋亡命运的影响
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摘要
水体富营养化以及由此造成的蓝藻爆发是当今人类面临的严重问题。这其中微囊藻属藻爆发引起的水体微囊藻毒素(MCs, microcystins)污染对人类的健康的影响尤其令人关注。例如,微囊藻毒素LR(MCLR, microcystin-LR)具有肝毒性、肾毒性、神经毒性等,且是毒性最强的微囊藻毒素之一。研究显示,MCLR既能造成细胞凋亡,又具有促肿瘤作用。然而,细胞暴露于MCLR后,其命运的决定因素尚待揭示。
蛋白磷酸酶2A(PP2A, protein phosphatase2A)是MCLR在细胞内的主要靶点。PP2A在细胞内具有重要的作用,参与几乎所有细胞生理活动,包括细胞增殖、细胞代谢、细胞分化和转变、DNA修复、细胞凋亡等。PP2A全酶由结构亚基(PP2A/A)、活性亚基(PP2A/C)以及调节亚基(PP2A/B)组成。其中,调节亚基决定PP2A全酶的下游底物、亚细胞定位以及具体的生理功能。目前已发现有75种PP2A全酶,各全酶都具有众多的底物。此外,还有一小部分PP2A/C亚基与a4蛋白结合但只具有较低的活性。这一结合状态与细胞在应激状态下对PP2A活性的调节具有重要的关联。
已有研究表明,MCLR直接与PP2A的活性亚基(PP2A/C)结合而造成的PP2A活性损失是MCLR造成细胞损伤的重要机制。但是,除开直接与PP2A/C结合以抑制其活性之外,MCLR是否影响PP2A其他亚基,以及MCLR如何具体影响细胞内PP2A全酶的活性则尚不明晰。此外,因为PP2A具有重要的生理功能,细胞在应激状态下对于PP2A的活性具有密切的调控,例如PP2A/C磷酸化、甲基化等翻译后修饰；产生神经酰胺后激活一部分PP2A(CAPP, ceramide activated protein phosphatase);α4蛋白与低活性PP2A解离以代偿活性损失等。由此我们提问：细胞应对MCLR的影响会产生哪些调节机制；这些调节机制是否足够代偿MCLR对细胞内PP2A的活性抑制作用,以及随之会产生哪些细胞学效应?
根据前期实验的蛋白质组学研究发现,细胞暴露于MC后,细胞内众多信号蛋白发生改变,并且这些信号蛋白大多与PP2A相关。由此本研究假设,细胞暴露于MCLR后,细胞内PP2A的活性,尤其是其全酶的活性,以及细胞对PP2A的调节机制,对于细胞命运的决定具有重要的作用。本研究选取人胚肾细胞系(HEK293, Human Embryonic Kidney293)这一肾脏来源的细胞作为研究对象,运用免疫印迹、免疫共沉淀、免疫荧光等方法,研究在MCLR对其细胞活力没有严重致死效应的条件下,HEK293细胞内PP2A亚基水平和活性的变化、PP2A底物磷酸化水平、PP2A活性调节机制、细胞骨架和细胞黏连蛋白的形态、细胞命运的选择。此外,本研究还选取小鼠作为活体研究对象,验证MCLR的肾脏毒性。
主要结果：
1. MCLR直接与HEK293细胞内PP2A/C亚基结合。在本实验浓度下,MCLR对细胞活力有下调的趋势,但并无严重的抑制效应。
2. MCLR不影响细胞内PP2A/A, PP2A/C和PP2A/B56δ蛋白水平,但上调PP2A/B55α和PP2A/B56α蛋白水平；MCLR下调细胞内PP2A/C甲基化,但不影响其磷酸化；MCLR引起PP2A与其泛素连接酶Mid1解离；高浓度MCLR造成PP2A/A和PP2A/C部分解离；MCLR引起PP2A/B55α部分聚集于高尔基体,但对PP2A/C和PP2A/B56α亚基定位影响不明显；MCLR引起细胞内PP2A/C和α4蛋白解离,并且造成α4蛋白定位于细胞核。
3. MCLR对细胞内PP2A总体活性影响呈低浓度刺激活性、高浓度抑制活性。
4. MCLR引起HEK293细胞生成神经酰胺。用神经酰胺合成酶抑制剂DESI共处理细胞后,MCLR引起的PP2A/B55α和PP2A/B56α蛋白水平上调效应消除；低浓度MCLR引起PP2A活性上调效应消除；高浓度MCLR对PP2A的活性抑制作用增强,以致PP2A活性几乎完全被抑制。
5. MCLR引起PP2A/B56a全酶的下游底物c-Myc磷酸化降低,但不影响其蛋白水平；PP2A/B56a全酶下游底物Bad蛋白水平升高,磷酸化比例降低。MCLR还引起凋亡相关蛋白Bcl-2蛋白水平降低,但不影响Bax蛋白水平。与DESI共处理后,MCLR对Bcl-2和Bad蛋白水平的改变减弱。MCLR还引起p38MAPK以及JNK蛋白磷酸化上调。
6. MCLR引起HEK293细胞形态改变。MCLR引起细胞微丝蛋白解聚,中间纤维之一的波形蛋白和微管蛋白聚缩,这一现象与神经酰胺处理HEK293细胞后细胞骨架的改变相似。与DESI共处理后,MCLR对细胞骨架的改变减弱。MCLR还引起骨架相关蛋白Rac1和Mid1定位于细胞核。
7. MCLR引起HEK293细胞粘着斑蛋白形态改变,并引起细胞贴壁能力减弱。MCLR引起细胞核聚缩化和片段化,引起细胞凋亡。与DESI共处理后,MCLR对细胞贴壁的影响以及刺激细胞凋亡的效应减弱。
8.小鼠腹腔注射MCLR毒素后,肾脏可检测神经酰胺的生成,并可检测到升高的细胞凋亡。
主要结论：
MCLR不但能直接与HEK293细胞内PP2A结合,还能引起细胞对PP2A的调节作用,包括产生神经酰胺,PP2A/C与α4蛋白解离等。此外,MCLR对细胞骨架、细胞贴壁以及细胞凋亡产生的影响与神经酰胺相关,并且与α4蛋白与PP2A/C解离后失去原有功能的推论相符合。MCLR还能刺激小鼠肾脏产生神经酰胺并产生细胞凋亡。本实验结果显示PP2A全酶活性及细胞对PP2A的调节作用对于细胞暴露于MCLR的凋亡命运的决定具有重要的作用。
Eutrophication and blue alga bloom in waters are causing serious environmental disasters worldwide. One group of blue alga, microcystis, produces microcystins (MCs) in water bloom that pose severe hazard to human health due to their strong toxicity. Among them, microcystin-LR (MCLR) has hepatoxicity, nephrotoxicity and neurotoxicity, and is one of the most toxic member of MCs. Studies have revealed that MCLR can cause cell death, while can also promote carcinogenesis. However, under exposure of MCLR, the determinant factors of cell fate are not clear.
Protein phosphatase2A (PP2A) is a main target of MCLR. PP2A has essentially important functions in cells and is involved in almost all the cellular activities, such as cell proliferation, metabolism, differentiation, transformation, DNA repair and apoptosis. PP2A holoenzyme is comprised of a scaffold subunit (PP2A/A), a catalytic subunit (PP2A/C), and one of many regulatory subunits (PP2A/B). The regulatory subunit determines the substrates, sub-cellular localization and the function of PP2A holoenzyme. At least75kinds of PP2A holoenzymes have been found and each has a variety of substrates. Other than the classical combination, a small part of PP2A/C binds to a4protein and has lower activity than the other forms. However, this form of combination plays an important role in cellular regulation of PP2A activity when under stress.
Previous studies have found that the direct binding of MCLR to PP2A/C inhibits its phosphatase activity. This feature of MCLR has long been considered the major mechanism by which MCLR poses cytotoxicity. However, apart from the direct binding and thus inhibition of PP2A activity, other effects of MCLR on cellular PP2A holoenzymes are largely unknown. Moreover, because of the essential importance of PP2A, its activity is under tight regulation by the cells. So far, it has been found that the cells regulate PP2A activity by phosphorylation and methylation of PP2A/C, by generating ceramide which upregulates certain forms of PP2A holoenzyme (CAPP, ceramide activated protein phosphatase), as well as by dissociation of PP2A/C and α4protein. Therefore we ask, when under MCLR insult, by which mechanisms cells may regulate PP2A activity; is the regulatory effect enough to compensate the activity loss caused by MCLR; and what are the consequential cellular effects?
Previous proteomic studies have shown that under the exposure of MC, a large spectrum of signal proteins are altered. Importantly, most of those proteins are related to PP2A. Thus, we hypothesize that under the exposure of MCLR, the activity of PP2A, especially the activity of its holoenzyme, as well as the regulation of PP2A from the cells, play an important role in the fate determination of the cells. The present study utilizes Human Embryonic Kidney293(HEK293) cell line, to study the PP2A subunit and activity change, the phosphorylation of its substrates, the regulation of PP2A activity, the morphological change of cytoskeleton and focal adhesion, and cell fate, at the time when cells are treated with MCLR at concentrations that do not cause massive cell death. This study also uses mouse kidney as in vivo subject to reinforce some in vitro result.
Major findings
1. MCLR can directly bind to PP2A/C in HEK293cells. The concentrations of MCLR used in this study do not cause massive cell death, though tend to inhibit their viability.
2. MCLR does not affect the protein levels of PP2A/A, PP2A/C and PP2A/B56δ in HEK293cells, but upregulates the protein levels of PP2A/B55a and PP2A/B56a; MCLR downregulates the methylation and ubiquitination of PP2A/C, but does not affect its phosphorylation; MCLR causes PP2A/C dissociate from its ubiquitinligase Mid1; relative higher concentration of MCLR causes dissociation of PP2A/A and PP2A/C; MCLR causes PP2A/B55a locate to Golgi apparatus but not PP2A/B56a; MCLR causes the dissociation of PP2A/C and a4protein, and a4protein locate to nucleus, but not PP2A/C.
3. Relatively low concentrations of MCLR upregulate, while relatively high concentrations of MCLR inhibit cellular PP2A activity.
4. MCLR induces the generation of ceramide. Using desipramine (DESI) to inhibit the generation of ceramide can alleviate the upregulation of PP2A/B55a and PP2A/B56α on protein level, and the upregualtion of PP2A activity at relatively low MCLR concentration, while aggravate the inhibition of PP2A by relatively high concentration of MCLR treatment, till almost complete inhibition.
5. MCLR decreases of phosphorylation of c-Myc, a substrate of PP2A holoenzyme containing PP2A/B56a, while does not affect c-Myc protein level. MCLR upregulates the protein level, and decreases of phosphorylation ratio of Bad, another substrate of PP2A holoenzyme containing PP2A/B56a. MCLR also downregulates Bcl-2on protein level, but does not affect Bax. Under DESI co-treatment, the effects of MCLR on Bad and Bcl-2are abated. MCLR also upregulates the phosphorylation of p38MAPK and JNK.
6. MCLR changes the morphology of HEK293cells. MCLR causes the depolymerization of cell filamentsactin, and the contraction of vimentin and microtubulin. The phenotype is similar to cells treated only with C6-cereamide. The disruption of cytoskeleton is alleviated when co-treated with MCLR and DESI. MCLR also causes cytoskeleton-related proteins Racl and Midi locate to nucleus.
7. MCLR changes the morphology of viculin and disrupts the cell attachment to culture matrix. MCLR causes condensation and fragmentation of nuclei, indicating apoptosis. These effects are aborted when co-treated with DESI.
8. Ceramide generation and increased apoptosis can be found in mouse kidney after MCLR injection.
Major conclusion
Besides that MCLR can directly bind to PP2A in HEK293cells, MCLR can also stimulate regulatory of PP2A in the cells, including the generation of ceramide, as well as dissociation of PP2A/C and a4. Furthermore, MCLR affects the cytoskeleton stability, cell attachment and induces apoptosis of HEK293cells. These cellular effects are related with ceramide, and also consistent with the loss of a4function due to dissociation with PP2A/C. Moreover, MCLR can induce ceramide generation and apoptosis in mouse kidney. Therefore, the results suggest that the holoenzyme activity of PP2A, and cellularregulation of PP2A, may be essential for the apoptotic fate of HEK293cells under MCLR exposure.
蛋白磷酸酶2A(PP2A, protein phosphatase2A)是MCLR在细胞内的主要靶点。PP2A在细胞内具有重要的作用,参与几乎所有细胞生理活动,包括细胞增殖、细胞代谢、细胞分化和转变、DNA修复、细胞凋亡等。PP2A全酶由结构亚基(PP2A/A)、活性亚基(PP2A/C)以及调节亚基(PP2A/B)组成。其中,调节亚基决定PP2A全酶的下游底物、亚细胞定位以及具体的生理功能。目前已发现有75种PP2A全酶,各全酶都具有众多的底物。此外,还有一小部分PP2A/C亚基与a4蛋白结合但只具有较低的活性。这一结合状态与细胞在应激状态下对PP2A活性的调节具有重要的关联。
已有研究表明,MCLR直接与PP2A的活性亚基(PP2A/C)结合而造成的PP2A活性损失是MCLR造成细胞损伤的重要机制。但是,除开直接与PP2A/C结合以抑制其活性之外,MCLR是否影响PP2A其他亚基,以及MCLR如何具体影响细胞内PP2A全酶的活性则尚不明晰。此外,因为PP2A具有重要的生理功能,细胞在应激状态下对于PP2A的活性具有密切的调控,例如PP2A/C磷酸化、甲基化等翻译后修饰；产生神经酰胺后激活一部分PP2A(CAPP, ceramide activated protein phosphatase);α4蛋白与低活性PP2A解离以代偿活性损失等。由此我们提问：细胞应对MCLR的影响会产生哪些调节机制；这些调节机制是否足够代偿MCLR对细胞内PP2A的活性抑制作用,以及随之会产生哪些细胞学效应?
根据前期实验的蛋白质组学研究发现,细胞暴露于MC后,细胞内众多信号蛋白发生改变,并且这些信号蛋白大多与PP2A相关。由此本研究假设,细胞暴露于MCLR后,细胞内PP2A的活性,尤其是其全酶的活性,以及细胞对PP2A的调节机制,对于细胞命运的决定具有重要的作用。本研究选取人胚肾细胞系(HEK293, Human Embryonic Kidney293)这一肾脏来源的细胞作为研究对象,运用免疫印迹、免疫共沉淀、免疫荧光等方法,研究在MCLR对其细胞活力没有严重致死效应的条件下,HEK293细胞内PP2A亚基水平和活性的变化、PP2A底物磷酸化水平、PP2A活性调节机制、细胞骨架和细胞黏连蛋白的形态、细胞命运的选择。此外,本研究还选取小鼠作为活体研究对象,验证MCLR的肾脏毒性。
主要结果：
1. MCLR直接与HEK293细胞内PP2A/C亚基结合。在本实验浓度下,MCLR对细胞活力有下调的趋势,但并无严重的抑制效应。
2. MCLR不影响细胞内PP2A/A, PP2A/C和PP2A/B56δ蛋白水平,但上调PP2A/B55α和PP2A/B56α蛋白水平；MCLR下调细胞内PP2A/C甲基化,但不影响其磷酸化；MCLR引起PP2A与其泛素连接酶Mid1解离；高浓度MCLR造成PP2A/A和PP2A/C部分解离；MCLR引起PP2A/B55α部分聚集于高尔基体,但对PP2A/C和PP2A/B56α亚基定位影响不明显；MCLR引起细胞内PP2A/C和α4蛋白解离,并且造成α4蛋白定位于细胞核。
3. MCLR对细胞内PP2A总体活性影响呈低浓度刺激活性、高浓度抑制活性。
4. MCLR引起HEK293细胞生成神经酰胺。用神经酰胺合成酶抑制剂DESI共处理细胞后,MCLR引起的PP2A/B55α和PP2A/B56α蛋白水平上调效应消除；低浓度MCLR引起PP2A活性上调效应消除；高浓度MCLR对PP2A的活性抑制作用增强,以致PP2A活性几乎完全被抑制。
5. MCLR引起PP2A/B56a全酶的下游底物c-Myc磷酸化降低,但不影响其蛋白水平；PP2A/B56a全酶下游底物Bad蛋白水平升高,磷酸化比例降低。MCLR还引起凋亡相关蛋白Bcl-2蛋白水平降低,但不影响Bax蛋白水平。与DESI共处理后,MCLR对Bcl-2和Bad蛋白水平的改变减弱。MCLR还引起p38MAPK以及JNK蛋白磷酸化上调。
6. MCLR引起HEK293细胞形态改变。MCLR引起细胞微丝蛋白解聚,中间纤维之一的波形蛋白和微管蛋白聚缩,这一现象与神经酰胺处理HEK293细胞后细胞骨架的改变相似。与DESI共处理后,MCLR对细胞骨架的改变减弱。MCLR还引起骨架相关蛋白Rac1和Mid1定位于细胞核。
7. MCLR引起HEK293细胞粘着斑蛋白形态改变,并引起细胞贴壁能力减弱。MCLR引起细胞核聚缩化和片段化,引起细胞凋亡。与DESI共处理后,MCLR对细胞贴壁的影响以及刺激细胞凋亡的效应减弱。
8.小鼠腹腔注射MCLR毒素后,肾脏可检测神经酰胺的生成,并可检测到升高的细胞凋亡。
主要结论：
MCLR不但能直接与HEK293细胞内PP2A结合,还能引起细胞对PP2A的调节作用,包括产生神经酰胺,PP2A/C与α4蛋白解离等。此外,MCLR对细胞骨架、细胞贴壁以及细胞凋亡产生的影响与神经酰胺相关,并且与α4蛋白与PP2A/C解离后失去原有功能的推论相符合。MCLR还能刺激小鼠肾脏产生神经酰胺并产生细胞凋亡。本实验结果显示PP2A全酶活性及细胞对PP2A的调节作用对于细胞暴露于MCLR的凋亡命运的决定具有重要的作用。
Eutrophication and blue alga bloom in waters are causing serious environmental disasters worldwide. One group of blue alga, microcystis, produces microcystins (MCs) in water bloom that pose severe hazard to human health due to their strong toxicity. Among them, microcystin-LR (MCLR) has hepatoxicity, nephrotoxicity and neurotoxicity, and is one of the most toxic member of MCs. Studies have revealed that MCLR can cause cell death, while can also promote carcinogenesis. However, under exposure of MCLR, the determinant factors of cell fate are not clear.
Protein phosphatase2A (PP2A) is a main target of MCLR. PP2A has essentially important functions in cells and is involved in almost all the cellular activities, such as cell proliferation, metabolism, differentiation, transformation, DNA repair and apoptosis. PP2A holoenzyme is comprised of a scaffold subunit (PP2A/A), a catalytic subunit (PP2A/C), and one of many regulatory subunits (PP2A/B). The regulatory subunit determines the substrates, sub-cellular localization and the function of PP2A holoenzyme. At least75kinds of PP2A holoenzymes have been found and each has a variety of substrates. Other than the classical combination, a small part of PP2A/C binds to a4protein and has lower activity than the other forms. However, this form of combination plays an important role in cellular regulation of PP2A activity when under stress.
Previous studies have found that the direct binding of MCLR to PP2A/C inhibits its phosphatase activity. This feature of MCLR has long been considered the major mechanism by which MCLR poses cytotoxicity. However, apart from the direct binding and thus inhibition of PP2A activity, other effects of MCLR on cellular PP2A holoenzymes are largely unknown. Moreover, because of the essential importance of PP2A, its activity is under tight regulation by the cells. So far, it has been found that the cells regulate PP2A activity by phosphorylation and methylation of PP2A/C, by generating ceramide which upregulates certain forms of PP2A holoenzyme (CAPP, ceramide activated protein phosphatase), as well as by dissociation of PP2A/C and α4protein. Therefore we ask, when under MCLR insult, by which mechanisms cells may regulate PP2A activity; is the regulatory effect enough to compensate the activity loss caused by MCLR; and what are the consequential cellular effects?
Previous proteomic studies have shown that under the exposure of MC, a large spectrum of signal proteins are altered. Importantly, most of those proteins are related to PP2A. Thus, we hypothesize that under the exposure of MCLR, the activity of PP2A, especially the activity of its holoenzyme, as well as the regulation of PP2A from the cells, play an important role in the fate determination of the cells. The present study utilizes Human Embryonic Kidney293(HEK293) cell line, to study the PP2A subunit and activity change, the phosphorylation of its substrates, the regulation of PP2A activity, the morphological change of cytoskeleton and focal adhesion, and cell fate, at the time when cells are treated with MCLR at concentrations that do not cause massive cell death. This study also uses mouse kidney as in vivo subject to reinforce some in vitro result.
Major findings
1. MCLR can directly bind to PP2A/C in HEK293cells. The concentrations of MCLR used in this study do not cause massive cell death, though tend to inhibit their viability.
2. MCLR does not affect the protein levels of PP2A/A, PP2A/C and PP2A/B56δ in HEK293cells, but upregulates the protein levels of PP2A/B55a and PP2A/B56a; MCLR downregulates the methylation and ubiquitination of PP2A/C, but does not affect its phosphorylation; MCLR causes PP2A/C dissociate from its ubiquitinligase Mid1; relative higher concentration of MCLR causes dissociation of PP2A/A and PP2A/C; MCLR causes PP2A/B55a locate to Golgi apparatus but not PP2A/B56a; MCLR causes the dissociation of PP2A/C and a4protein, and a4protein locate to nucleus, but not PP2A/C.
3. Relatively low concentrations of MCLR upregulate, while relatively high concentrations of MCLR inhibit cellular PP2A activity.
4. MCLR induces the generation of ceramide. Using desipramine (DESI) to inhibit the generation of ceramide can alleviate the upregulation of PP2A/B55a and PP2A/B56α on protein level, and the upregualtion of PP2A activity at relatively low MCLR concentration, while aggravate the inhibition of PP2A by relatively high concentration of MCLR treatment, till almost complete inhibition.
5. MCLR decreases of phosphorylation of c-Myc, a substrate of PP2A holoenzyme containing PP2A/B56a, while does not affect c-Myc protein level. MCLR upregulates the protein level, and decreases of phosphorylation ratio of Bad, another substrate of PP2A holoenzyme containing PP2A/B56a. MCLR also downregulates Bcl-2on protein level, but does not affect Bax. Under DESI co-treatment, the effects of MCLR on Bad and Bcl-2are abated. MCLR also upregulates the phosphorylation of p38MAPK and JNK.
6. MCLR changes the morphology of HEK293cells. MCLR causes the depolymerization of cell filamentsactin, and the contraction of vimentin and microtubulin. The phenotype is similar to cells treated only with C6-cereamide. The disruption of cytoskeleton is alleviated when co-treated with MCLR and DESI. MCLR also causes cytoskeleton-related proteins Racl and Midi locate to nucleus.
7. MCLR changes the morphology of viculin and disrupts the cell attachment to culture matrix. MCLR causes condensation and fragmentation of nuclei, indicating apoptosis. These effects are aborted when co-treated with DESI.
8. Ceramide generation and increased apoptosis can be found in mouse kidney after MCLR injection.
Major conclusion
Besides that MCLR can directly bind to PP2A in HEK293cells, MCLR can also stimulate regulatory of PP2A in the cells, including the generation of ceramide, as well as dissociation of PP2A/C and a4. Furthermore, MCLR affects the cytoskeleton stability, cell attachment and induces apoptosis of HEK293cells. These cellular effects are related with ceramide, and also consistent with the loss of a4function due to dissociation with PP2A/C. Moreover, MCLR can induce ceramide generation and apoptosis in mouse kidney. Therefore, the results suggest that the holoenzyme activity of PP2A, and cellularregulation of PP2A, may be essential for the apoptotic fate of HEK293cells under MCLR exposure.
引文
Ahn, C.S., Han, J.A., Lee, H.S., Lee, S., and Pai, H.S. (2011). The PP2A regulatory subunit Tap46, a component of the TOR signaling pathway, modulates growth and metabolism in plants. Plant Cell 23,185-209.
Aranda-Orgilles, B., Aigner, J., Kunath, M., Lurz, R., Schneider, R., and Schweiger, S. (2008). Active transport of the ubiquitin ligase MIDI along the microtubules is regulated by protein phosphatase 2A. PLoS One 3, e3507.
Aranda-Orgilles, B., Rutschow, D., Zeller, R., Karagiannidis, A.I., Kohler, A., Chen, C, Wilson, T., Krause, S., Roepcke, S., Lilley, D., et al. (2011). Protein phosphatase 2A (PP2A)-specific ubiquitin ligase MID1 is a sequence-dependent regulator of translation efficiency controlling 3-phosphoinositide-dependent protein kinase-1 (PDPK-1). J Biol Chem 286,39945-39957.
Arnold, H.K., and Sears, R.C. (2006). Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation. Mol Cell Biol 26,2832-2844.
Arroyo, J.D., and Hahn, W.C. (2005). Involvement of PP2A in viral and cellular transformation. Oncogene 24,7746-7755.
Basu, S. (2011). PP2A in the regulation of cell motility and invasion. Curr Protein Pept Sci 12,3-11.
Bradford, M.M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72,248-254.
Calin, G.A., di Iasio, M.G., Caprini, E., Vorechovsky, I., Natali, P.G., Sozzi, G, Croce, C.M., Barbanti-Brodano, G, Russo, G, and Negrini, M. (2000). Low frequency of alterations of the alpha (PPP2R1A) and beta (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene 19, 1191-1195.
Campos, A., and Vasconcelos, V. (2010). Molecular mechanisms of microcystin toxicity in animal cells. Int J Mol Sci 11,268-287.
Chalfant, C.E., Szulc, Z., Roddy, P., Bielawska, A., and Hannun, Y.A. (2004). The structural requirements for ceramide activation of serine-threonine protein phosphatases. J Lipid Res 45,496-506.
Chang, L., and Goldman, R.D. (2004). Intermediate filaments mediate cytoskeletal crosstalk. Nat Rev Mol Cell Biol 5,601-613.
Chen, D.N., Zeng, J., Wang, F., Zheng, W., Tu, W.W., Zhao, J.S., and Xu, J. (2012). Hyperphosphorylation of intermediate filament proteins is involved in microcystin-LR-induced toxicity in HL7702 cells. Toxicol Lett 214,192-199.
Chen, J., Xie, P., Li, L., and Xu, J. (2009). First identification of the hepatotoxic microcystins in the serum of a chronically exposed human population together with indication of hepatocellular damage. Toxicol Sci 108,81-89.
Chen, L., Zhang, X., Zhou, W., Qiao, Q., Liang, H., Li, G., Wang, J., and Cai, F. (2013). The interactive effects of cytoskeleton disruption and mitochondria dysfunction lead to reproductive toxicity induced by microcystin-LR. PLoS One 8, e53949.
Chen LP, L.Y., Li DC, Zhu XN, Yang P, Li WX, Zhu W, Zhao J, Li XD, Xiao YM, Zhang Y, Xing XM, Wang Q, Zhang B, Lin YC, Zeng JL, Zhang SX, Liu CX, Li ZF, Zeng XW, Lin ZN, Zhuang ZX, Chen W. (2011). a4 is highly expressed in carcinogen-transformed human cells and primary human cancers. Oncogene 30, 2943-2953.
Chen, T., Wang, Q., Cui, J., Yang, W., Shi, Q., Hua, Z., Ji, J., and Shen, P. (2005). Induction of apoptosis in mouse liver by microcystin-LR:a combined transcriptomic, proteomic, and simulation strategy. Mol Cell Proteomics 4, 958-974.
Cho, U.S., and Xu, W. (2007). Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 445,53-57.
Codd, G.A., Morrison, L.F., and Metcalf, J.S. (2005). Cyanobacterial toxins:risk management for health protection. Toxicol Appl Pharmacol 203,264-272.
Coll, J.L., Ben-Ze'ev, A., Ezzell, R.M., Rodriguez Fernandez, J.L., Baribault, H., Oshima, R.G, and Adamson, E.D. (1995). Targeted disruption of vinculin genes in F9 and embryonic stem cells changes cell morphology, adhesion, and locomotion. Proc Natl Acad Sci U S A 92,9161-9165.
Dawson, R.M. (1998). The toxicology of microcystins. Toxicon 36,953-962.
Delgado, L.F., Charles, P., Glucina, K., and Morlay, C. (2012). The removal of endocrine disrupting compounds, pharmaceutically activated compounds and cyanobacterial toxins during drinking water preparation using activated carbon--a review. Sci Total Environ 435-436,509-525.
Dias, E., Andrade, M., Alverca, E., Pereira, P., Batoreu, M.C., Jordan, P., and Silva, M.J. (2009). Comparative study of the cytotoxic effect of microcistin-LR and purified extracts from Microcystis aeruginosa on a kidney cell line. Toxicon 53,487-495.
Ding, W.X., Shen, H.M., and Ong, C.N. (2000a). Critical role of reactive oxygen species and mitochondrial permeability transition in microcystin-induced rapid apoptosis in rat hepatocytes. Hepatology 32,547-555.
Ding, W.X., Shen, H.M., and Ong, C.N. (2000b). Microcystic cyanobacteria extract induces cytoskeletal disruption and intracellular glutathione alteration in hepatocytes. Environ Health Perspect 108,605-609.
Ding, W.X., Shen, H.M., and Ong, C.N. (2001). Critical role of reactive oxygen species formation in microcystin-induced cytoskeleton disruption in primary cultured hepatocytes. J Toxicol Environ Health A 64,507-519.
Dobrowsky, R.T., Kamibayashi, C., Mumby, M.C., and Hannun, Y.A. (1993). Ceramide activates heterotrimeric protein phosphatase 2A. J Biol Chem 268,15523-15530.
Eichhorn, P.J., Creyghton, M.P., and Bernards, R. (2009). Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta 1795,1-15.
Embade, N., Valeron, P.F., Aznar, S., Lopez-Collazo, E., and Lacal, J.C. (2000). Apoptosis induced by Rac GTPase correlates with induction of FasL and ceramides production. Mol Biol Cell 11,4347-4358.
Etienne-Manneville, S., and Hall, A. (2002). Rho GTPases in cell biology. Nature 420, 629-635.
Ferrao-Filho Ada, S., Kozlowsky-Suzuki, B., and Azevedo, S.M. (2002). Accumulation of microcystins by a tropical zooplankton community. Aquat Toxicol 59,201-208.
Feurstein, D., Holst, K., Fischer, A., and Dietrich, D.R. (2009). Oatp-associated uptake and toxicity of microcystins in primary murine whole brain cells. Toxicol Appl Pharmacol 234,247-255.
Feurstein, D., Kleinteich, J., Heussner, A.H., Stemmer, K., and Dietrich, D.R. (2010). Investigation of microcystin congener-dependent uptake into primary murine neurons. Environ Health Perspect 118,1370-1375.
Fladmark, K.E., Brustugun, O.T., Hovland, R., Boe, R., Gjertsen, B.T., Zhivotovsky, B., and Doskeland, S.O. (1999). Ultrarapid caspase-3 dependent apoptosis induction by serine/threonine phosphatase inhibitors. Cell Death Differ 6,1099-1108.
Freeman, K.S. (2010). Harmful algal blooms. Musty warnings of toxicity. Environ Health Perspect 118, A473.
Frisch, S.M., and Screaton, R.A. (2001). Anoikis mechanisms. Curr Opin Cell Biol 13, 555-562.
Fu, W., Yu, Y., and Xu, L. (2009). Identification of temporal differentially expressed protein responses to microcystin in human amniotic epithelial cells. Chem Res Toxicol 22,41-51.
Fu, W.Y., Xu, L.H., and Yu, Y.N. (2005). Proteomic analysis of cellular response to microcystin in human amnion FL cells. J Proteome Res 4,2207-2215.
Fujiki, H., and Suganuma, M. (2011). Tumor promoters--microcystin-LR, nodularin and TNF-alpha and human cancer development. Anticancer Agents Med Chem 11, 4-18.
Galadari, S., Kishikawa, K., Kamibayashi, C., Mumby, M.C., and Hannun, Y.A. (1998). Purification and characterization of ceramide-activated protein phosphatases. Biochemistry 37,11232-11238.
Gehringer, M.M. (2004). Microcystin-LR and okadaic acid-induced cellular effects:a dualistic response. FEBS Lett 557,1-8.
Grossmann, J. (2002). Molecular mechanisms of "detachment-induced apoptosis--Anoikis". Apoptosis 7,247-260.
Hamm-Alvarez, S.F., Wei, X., Berndt, N., and Runnegar, M. (1996). Protein phosphatases independently regulate vesicle movement and microtubule subpopulations in hepatocytes. Am J Physiol 271, C929-943.
Hannun, Y.A., and Luberto, C. (2000). Ceramide in the eukaryotic stress response. Trends Cell Biol 10,73-80.
Hannun, Y.A., and Obeid, L.M. (1997). Ceramide and the eukaryotic stress response. Biochem Soc Trans 25,1171-1175.
Hannun, Y.A., and Obeid, L.M. (2008). Principles of bioactive lipid signalling:lessons from sphingolipids. Nat Rev Mol Cell Biol 9,139-150.
Honkanen, R.E., Zwiller, J., Moore, R.E., Daily, S.L., Khatra, B.S., Dukelow, M., and Boynton, A.L. (1990). Characterization of microcystin-LR, a potent inhibitor of type 1 and type 2A protein phosphatases. J Biol Chem 265,19401-19404.
Hou, Q., Jin, J., Zhou, H., Novgorodov, S.A., Bielawska, A., Szulc, Z.M., Hannun, Y.A., Obeid, L.M., and Hsu, Y.T. (2011). Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis. J Lipid Res 52,278-288.
Humphries, J.D., Wang, P., Streuli, C., Geiger, B., Humphries, M.J., and Ballestrem, C. (2007). Vinculin controls focal adhesion formation by direct interactions with talin and actin. J Cell Biol 179,1043-1057.
Inui, S., Sanjo, H., Maeda, K., Yamamoto, H., Miyamoto, E., and Sakaguchi, N. (1998). Ig receptor binding protein 1 (alpha4) is associated with a rapamycin-sensitive signal transduction in lymphocytes through direct binding to the catalytic subunit of protein phosphatase 2 A. Blood 92,539-546.
Janssens, V., and Goris, J. (2001). Protein phosphatase 2A:a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353,417-439.
Janssens, V., and Rebollo, A. (2012). The role and therapeutic potential of Ser/Thr phosphatase PP2A in apoptotic signalling networks in human cancer cells. Curr Mol Med 12,268-287.
Jochimsen, E.M., Carmichael, W.W., An, J.S., Cardo, D.M., Cookson, S.T., Holmes, C.E., Antunes, M.B., de Melo Filho, D.A., Lyra, T.M., Barreto, V.S., et al. (1998). Liver failure and death after exposure to microcystins at a hemodialysis center in Brazil. N Engl J Med 338,873-878.
Junttila, M.R., Li, S.P., and Westermarck, J. (2008). Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J 22, 954-965.
Junttila, M.R., Puustinen, P., Niemela, M., Ahola, R., Arnold, H., Bottzauw, T., Ala-aho, R., Nielsen, C., Ivaska, J., Taya, Y., et al. (2007). CIP2A inhibits PP2A in human malignancies. Cell 130,51-62.
Kim, B.C., and Kim, J.H. (1998). Exogenous C2-ceramide activates c-fos serum response element via Rac-dependent signalling pathway. Biochem J 330 (Pt 2), 1009-1014.
Klintworth, H., Newhouse, K., Li, T., Choi, W.S., Faigle, R., and Xia, Z. (2007). Activation of c-Jun N-terminal protein kinase is a common mechanism underlying paraquat- and rotenone-induced dopaminergic cell apoptosis. Toxicol Sci 97, 149-162.
Komatsu, M., Furukawa, T., Ikeda, R., Takumi, S., Nong, Q., Aoyama, K., Akiyama, S., Keppler, D., and Takeuchi, T. (2007). Involvement of mitogen-activated protein kinase signaling pathways in microcystin-LR-induced apoptosis after its selective uptake mediated by OATP1B1 and OATP1B3. Toxicol Sci 97,407-416.
Kong, M., Bui, T.V., Ditsworth, D., Gruber, J.J., Goncharov, D., Krymskaya, V.P., Lindsten, T., and Thompson, C.B. (2007). The PP2A-associated protein alpha4 plays a critical role in the regulation of cell spreading and migration. J Biol Chem 282,29712-29720.
Kong, M., Ditsworth, D., Lindsten, T., and Thompson, C.B. (2009). Alpha4 is an essential regulator of PP2A phosphatase activity. Mol Cell 36,51-60.
Kong, M., Fox, C.J., Mu, J., Solt, L., Xu, A., Cinalli, R.M., Birnbaum, M.J., Lindsten, T., and Thompson, C.B. (2004). The PP2A-associated protein alpha4 is an essential inhibitor of apoptosis. Science 306,695-698.
Laine, A., Come, C., Junttila, M.R., Puustinen, P., Niemela, M., Boulfroy, M., Thezenas, S., Darbon, J.M., Isola, J., Kallioniemi, O.P., et al. (2008). Involvement of CIP2A, a novel human oncoprotein inhibiting protein phosphatase 2A (PP2A), in breast cancer. Febs Journal 275,454-454.
Laine A, S.H., Come C, Rosenfeldt MT, Zwolinska A, Niemela M, Khanna A, Chan EK, Kahari VM, Kellokumpu-Lehtinen PL, Sansom OJ, Evan GI, Junttila MR, Ryan KM, Marine JC, Joensuu H, Westermarck J. (2013). Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1. Cancer Discov 3,182-197.
Lezcano, N., Sedan, D., Lucotti, I., Giannuzzi, L., Vittone, L., Andrinolo, D., and Mundina-Weilenmann, C. (2012). Subchronic microcystin-LR exposure increased hepatic apoptosis and induced compensatory mechanisms in mice. J Biochem Mol Toxicol 26,131-138.
Li, G, Cai, F., Yan, W., Li, C., and Wang, J. (2012a). A proteomic analysis of MCLR-induced neurotoxicity:implications for Alzheimer's disease. Toxicol Sci 127,485-495.
Li, T., Huang, P., Liang, J., Fu, W., Guo, Z., and Xu, L. (2011a). Microcystin-LR (MCLR) Induces a Compensation of PP2A Activity Mediated by alpha4 Protein in HEK293 Cells. Int J Biol Sci 7,740-752.
Li, T., Ting, L., Wang, H., Li, N., Fu, ., Guo, Z., and Xu, L. (2012b). Microcystin-LR induces ceramide to regulate PP2A and destabilize cytoskeleton in HEK293 cells. Toxicol Sci 128,147-157.
Li, Y., Chen, J.A., Zhao, Q., Pu, C., Qiu, Z., Zhang, R., and Shu, W. (2011b). A cross-sectional investigation of chronic exposure to microcystin in relationship to childhood liver damage in the Three Gorges Reservoir Region, China. Environ Health Perspect 119,1483-1488.
Lin, S.S., Bassik, M.C., Suh, H., Nishino, M., Arroyo, J.D., Hahn, W.C., Korsmeyer, S.J., and Roberts, T.M. (2006). PP2A regulates BCL-2 phosphorylation and proteasome-mediated degradation at the endoplasmic reticulum. J Biol Chem 281, 23003-23012.
Lowe, M., Gonatas, N.K., and Warren, G (2000). The mitotic phosphorylation cycle of the cis-Golgi matrix protein GM130. J Cell Biol 149,341-356.
MacKintosh, C., Beattie, K.A., Klumpp, S., Cohen, P., and Codd, G.A. (1990). Cyanobacterial microcystin-LR is a potent and specific inhibitor of protein phosphatases 1 and 2A from both mammals and higher plants. FEBS Lett 264, 187-192.
McConnell, J.L., Gomez, R.J., McCorvey, L.R., Law, B.K., and Wadzinski, B.E. (2007). Identification of a PP2A-interacting protein that functions as a negative regulator of phosphatase activity in the ATM/ATR signaling pathway. Oncogene 26,6021-6030.
McConnell, J.L., Watkins, G.R., Soss, S.E., Franz, H.S., McCorvey, L.R., Spiller, B.W., Chazin, W.J., and Wadzinski, B.E. (2010). Alpha4 is a ubiquitin-binding protein that regulates protein serine/threonine phosphatase 2A ubiquitination. Biochemistry 49,1713-1718.
Meng, G, Sun, Y., Fu, W., Guo, Z., and Xu, L. (2011). Microcystin-LR induces cytoskeleton system reorganization through hyperphosphorylation of tau and HSP27 via PP2A inhibition and subsequent activation of the p38 MAPK signaling pathway in neuroendocrine (PC 12) cells. Toxicology 290,218-229.
Mukhopadhyay, A., Saddoughi, S.A., Song, P., Sultan, I., Ponnusamy, S., Senkal, C.E., Snook, C.F., Arnold, H.K., Sears, R.C., Hannun, Y.A., et al. (2009). Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2 A activity and signaling. FASEB J 23,751-763.
Mumby, M. (2007). PP2A:unveiling a reluctant tumor suppressor. Cell 130,21-24.
Murata, K., Wu, J., and Brautigan, D.L. (1997). B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc Natl Acad Sci U S A 94,10624-10629.
Nagendra, D.C., Burke, J.,3rd, Maxwell, GL., and Risinger, J.I. (2012). PPP2R1A mutations are common in the serous type of endometrial cancer. Mol Carcinog 51, 826-831.
Nanahoshi, M., Tsujishita, Y., Tokunaga, C., Inui, S., Sakaguchi, N., Hara, K., and Yonezawa, K. (1999). Alpha4 protein as a common regulator of type 2A-related serine/threonine protein phosphatases. FEBS Lett 446,108-112.
Niemela, M., Kauko, O., Sihto, H., Mpindi, J.P., Nicorici, D., Pernila, P., Kallioniemi, O.P., Joensuu, H., Hautaniemi, S., and Westermarck, J. (2012). CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes. Oncogene 31,4266-4278.
Oberhammer, F.A., Hochegger, K., Froschl, G., Tiefenbacher, R., and Pavelka, M. (1994). Chromatin condensation during apoptosis is accompanied by degradation of lamin A+B, without enhanced activation of cdc2 kinase. J Cell Biol 126, 827-837.
Ohta, T., Nishiwaki, R., Yatsunami, J., Komori, A., Suganuma, M., and Fujiki, H. (1992). Hyperphosphorylation of cytokeratins 8 and 18 by microcystin-LR, a new liver tumor promoter, in primary cultured rat hepatocytes. Carcinogenesis 13, 2443-2447.
Prendergast, G.C. (1999). Mechanisms of apoptosis by c-Myc. Oncogene 18, 2967-2987.
Prickett, T.D., and Brautigan, D.L. (2007). Cytokine activation of p38 mitogen-activated protein kinase and apoptosis is opposed by alpha-4 targeting of protein phosphatase 2A for site-specific dephosphorylation of MEK3. Mol Cell Biol 27,4217-4227.
Ruediger, R., Pham, H.T., and Walter, G. (2001). Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the A alpha subunit gene. Oncogene 20,10-15.
Runnegar, M., Berndt, N., Kong, S.M., Lee, E.Y., and Zhang, L. (1995). In vivo and in vitro binding of microcystin to protein phosphatases 1 and 2A. Biochem Biophys Res Commun 216,162-169.
Ruvolo, P.P., Clark, W., Mumby, M., Gao, F., and May, W.S. (2002). A functional role for the B56 alpha-subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2 phosphorylation status and function. J Biol Chem 277, 22847-22852.
Saddoughi, S.A., Gencer, S., Peterson, Y.K., Ward, K.E., Mukhopadhyay, A., Oaks, J., Bielawski, J., Szulc, Z.M., Thomas, R.J., Selvam, S.P., et al. (2013). Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Mol Med 5, 105-121.
Saito, T., Okano, K., Park, H.D., Itayama, T., Inamori, Y, Neilan, B.A., Burns, B.P., and Sugiura, N. (2003). Detection and sequencing of the microcystin LR-degrading gene, mlrA, from new bacteria isolated from Japanese lakes. FEMS Microbiol Lett 229,271-276.
Sents, W., Ivanova, E., Lambrecht, C., Haesen, D., and Janssens, V. (2012). The biogenesis of active protein phosphatase 2A holoenzymes:a tightly regulated process creating phosphatase specificity. FEBS J 280,644-661.
Seshacharyulu, P., Pandey, P., Datta, K., and Batra, S.K. (2013). Phosphatase:PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Lett.
Sontag, E. (2001). Protein phosphatase 2A:the Trojan Horse of cellular signaling. Cell Signal 13,7-16.
Sun, Y, Meng, G.M., Guo, Z.L., and Xu, L.H. (2011). Regulation of heat shock protein 27 phosphorylation during microcystin-LR-induced cytoskeletal reorganization in a human liver cell line. Toxicol Lett 207,270-277.
Tamaki, M., Goi, T., Hirono, Y., Katayama, K., and Yamaguchi, A. (2004). PPP2R1B gene alterations inhibit interaction of PP2A-Abeta and PP2A-C proteins in colorectal cancers. Oncol Rep 11,655-659.
Trockenbacher, A., Suckow, V., Foerster, J., Winter, J., Krauss, S., Ropers, H.H., Schneider, R., and Schweiger, S. (2001). MIDI, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nat Genet 29,287-294.
Tsuji, K., Naito, S., Kondo, F., Ishikawa, N., Watanabe, M.F., Suzuki, M., and Harada, K. (1994). Stability of microcystins from cyanobacteria:effect of light on decomposition and isomerization. Environ Sci Technol 28,173-177.
Turowski, P., Myles, T., Hemmings, B.A., Fernandez, A., and Lamb, N.J. (1999). Vimentin dephosphorylation by protein phosphatase 2A is modulated by the targeting subunit B55. Mol Biol Cell 10,1997-2015.
Van Hoof, C., and Goris, J. (2003). Phosphatases in apoptosis:to be or not to be, PP2A is in the heart of the question. Biochim Biophys Acta 1640,97-104.
Wang, M., Chan, L.L., Si, M., Hong, H., and Wang, D. (2010). Proteomic analysis of hepatic tissue of zebrafish (Danio rerio) experimentally exposed to chronic microcystin-LR. Toxicol Sci 113,60-69.
Wang, N., Leung, H.T., Mazalouskas, M.D., Watkins, G.R., Gomez, R.J., and Wadzinski, B.E. (2012). Essential roles of the Tap42-regulated protein phosphatase 2A (PP2A) family in wing imaginal disc development of Drosophila melanogaster. PLoS One 7, e38569.
Weng, D., Lu, Y, Wei, Y, Liu, Y, and Shen, P. (2007). The role of ROS in microcystin-LR-induced hepatocyte apoptosis and liver injury in mice. Toxicology 232,15-23.
Widau, R.C., Jin, Y, Dixon, S.A., Wadzinski, B.E., and Gallagher, P.J. (2010). Protein phosphatase 2A (PP2A) holoenzymes regulate death-associated protein kinase (DAPK) in ceramide-induced anoikis. J Biol Chem 285,13827-13838.
Xia, Z., Dickens, M., Raingeaud, J., Davis, R.J., and Greenberg, M.E. (1995). Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270,1326-1331.
Xie, L., Xie, P., Guo, L., Li, L., Miyabara, Y, and Park, H.D. (2005). Organ distribution and bioaccumulation of microcystins in freshwater fish at different trophic levels from the eutrophic Lake Chaohu, China. Environ Toxicol 20,293-300.
Xing, Y, Li, Z., Chen, Y, Stock, J.B., Jeffrey, P.D., and Shi, Y (2008). Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell 133, 154-163.
Xing, Y, Xu, Y, Chen, Y., Jeffrey, P.D., Chao, Y, Lin, Z., Li, Z., Strack, S., Stock, J.B., and Shi, Y (2006). Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell 127,341-353.
Yoo, S.J., Jimenez, R.H., Sanders, J.A., Boylan, J.M., Brautigan, D.L., and Gruppuso, P.A. (2008). The alpha4-containing form of protein phosphatase 2A in liver and hepatic cells. J Cell Biochem 105,290-300.
Yuan, M., Carmichael, W.W., and Hilborn, E.D. (2006). Microcystin analysis in human sera and liver from human fatalities in Caruaru, Brazil 1996. Toxicon 48,627-640.
Zegura, B., Straser, A., and Filipic, M. (2011). Genotoxicity and potential carcinogenicity of cyanobacterial toxins-a review. Mutat Res 727,16-41.
Zeidan, Y.H., and Hannun, Y.A. (2010). The acid sphingomyelinase/ceramide pathway: biomedical significance and mechanisms of regulation. Curr Mol Med 10,454-466.
Zeidan, Y.H., Jenkins, R.W., and Hannun, Y.A. (2008). Remodeling of cellular cytoskeleton by the acid sphingomyelinase/ceramide pathway. J Cell Biol 181, 335-350.
Zhang, X.X., Fu, Z., Zhang, Z., Miao, C., Xu, P., Wang, T., Yang, L., and Cheng, S. (2012). Microcystin-LR promotes melanoma cell invasion and enhances matrix metalloproteinase-2/-9 expression mediated by NF-kappaB activation. Environ Sci Technol 46,11319-11326.
Zhao, Y, Xie, P., and Fan, H. (2011). Genomic profiling of microRNAs and proteomics reveals an early molecular alteration associated with tumorigenesis induced by MC-LR in mice. Environ Sci Technol 46,34-41.
Zhou, J., Pham, H.T., Ruediger, R., and Walter, G. (2003). Characterization of the Aalpha and Abeta subunit isoforms of protein phosphatase 2A:differences in expression, subunit interaction, and evolution. Biochem J 369,387-398.
Zhu, Y., Zhong, X., Zheng, S., Ge, Z., Du, Q., and Zhang, S. (2005). Transformation of immortalized colorectal crypt cells by microcystin involving constitutive activation of Akt and MAPK cascade. Carcinogenesis 26,1207-1214.
Alayev, A., and Holz, M.K. (2013). mTOR signaling for biological control and cancer. J Cell Physiol.
Arnold, H.K., and Sears, R.C. (2006). Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation. Mol Cell Biol 26,2832-2844.
Baysal, B.E., Willett-Brozick, J.E., Taschner, P.E., Dauwerse, J.G., Devilee, P., and Devlin, B. (2001). A high-resolution integrated map spanning the SDHD gene at 11q23:a 1.1-Mb BAC contig, a partial transcript map and 15 new repeat polymorphisms in a tumour-suppressor region. Eur J Hum Genet 9,121-129.
Bradbury, P., Mahmassani, M., Zhong, J., Turner, K., Paul, A., Verrills, N.M., and O'Neill, G.M. (2012). PP2A phosphatase suppresses function of the mesenchymal invasion regulator NEDD9. Biochim Biophys Acta 1823,290-297.
Calin, G.A., di Iasio, M.G., Caprini, E., Vorechovsky, I., Natali, P.G., Sozzi, G, Croce, C.M., Barbanti-Brodano, G, Russo, G, and Negrini, M. (2000). Low frequency of alterations of the alpha (PPP2R1A) and beta (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene 19, 1191-1195.
Chen LP, L.Y., Li DC, Zhu XN, Yang P, Li WX, Zhu W, Zhao J, Li XD, Xiao YM, Zhang Y, Xing XM, Wang Q, Zhang B, Lin YC, Zeng JL, Zhang SX, Liu CX, Li ZF, Zeng XW, Lin ZN, Zhuang ZX, Chen W. (2011). a4 is highly expressed in carcinogen-transformed human cells and primary human cancers. Oncogene 30, 2943-2953.
Chen, W., Arroyo, J.D., Timmons, J.C., Possemato, R., and Hahn, W.C. (2005). Cancer-associated PP2A Aalpha subunits induce functional haploinsufficiency and tumorigenicity. Cancer Res 65,8183-8192.
Chen, W., Possemato, R., Campbell, K.T., Plattner, C.A., Pallas, D.C., and Hahn, W.C. (2004). Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell 5,127-136.
Cho, U.S., and Xu, W. (2007). Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 445,53-57.
Come C, L.A., Chanrion M, Edgren H, Mattila E, Liu X, Jonkers J, Ivaska J, Isola J, Darbon JM, Kallioniemi O, Thezenas S, Westermarck J. (2009). CIP2A Is Associated with Human Breast Cancer Aggressivity. Clin Cancer Res 15, 5092-5100.
Dupont, W.D., Breyer, J.P., Bradley, K.M., Schuyler, P.A., Plummer, W.D., Sanders, M.E., Page, D.L., and Smith, J.R. (2010). Protein phosphatase 2A subunit gene haplotypes and proliferative breast disease modify breast cancer risk. Cancer 116, 8-19.
Eichhorn, P.J., Creyghton, M.P., and Bernards, R. (2009). Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta 1795,1-15.
Esplin, E.D., Ramos, P., Martinez, B., Tomlinson, G.E., Mumby, M.C., and Evans, GA. (2006). The glycine 90 to aspartate alteration in the Abeta subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function. Genes Chromosomes Cancer 45,182-190.
Fisher, B., Costantino, J.P., Wickerham, D.L., Redmond, C.K., Kavanah, M., Cronin, W.M., Vogel, V., Robidoux, A., Dimitrov, N., Atkins, J., et al. (1998). Tamoxifen for prevention of breast cancer:report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90,1371-1388.
Fu, W., Yu, Y., and Xu, L. (2009). Identification of temporal differentially expressed protein responses to microcystin in human amniotic epithelial cells. Chem Res Toxicol 22,41-51.
Fu, W.Y., Xu, L.H., and Yu, Y.N. (2005). Proteomic analysis of cellular response to microcystin in human amnion FL cells. J Proteome Res 4,2207-2215.
Gopalakrishna, R., Gundimeda, U., Fontana, J.A., and Clarke, R. (1999). Differential distribution of protein phosphatase 2 A in human breast carcinoma cell lines and its relation to estrogen receptor status. Cancer Lett 136,143-151.
Huang, P., Zheng, Y.F., and Xu, L.H. (2008). Oral administration of cyanobacterial bloom extract induced the altered expression of the PP2A, Bax, and Bcl-2 in mice. Environ Toxicol.
Hui, L., Rodrik, V., Pielak, R.M., Knirr, S., Zheng, Y, and Foster, D.A. (2005). mTOR-dependent suppression of protein phosphatase 2A is critical for phospholipase D survival signals in human breast cancer cells. J Biol Chem 280, 35829-35835.
Janssens, V., and Goris, J. (2001). Protein phosphatase 2A:a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353,417-439.
Janssens, V., and Rebollo, A. (2012). The role and therapeutic potential of Ser/Thr phosphatase PP2A in apoptotic signalling networks in human cancer cells. Curr Mol Med 12,268-287.
Junttila, M.R., Puustinen, P., Niemela, M., Ahola, R., Arnold, H., Bottzauw, T., Ala-aho, R., Nielsen, C., Ivaska, J., Taya, Y., et al. (2007). CIP2A inhibits PP2A in human malignancies. Cell 130,51-62.
Keen, J.C., Garrett-Mayer, E., Pettit, C., Mack, K.M., Manning, J., Herman, J.G., and Davidson, N.E. (2004). Epigenetic regulation of protein phosphatase 2A (PP2A), lymphotactin (XCL1) and estrogen receptor alpha (ER) expression in human breast cancer cells. Cancer Biol Ther 3,1304-1312.
Keen, J.C., Zhou, Q., Park, B.H., Pettit, C., Mack, K.M., Blair, B., Brenner, K., and Davidson, N.E. (2005). Protein phosphatase 2A regulates estrogen receptor alpha (ER) expression through modulation of ER mRNA stability. J Biol Chem 280, 29519-29524.
Kim, S.W., Jung, H.K., and Kim, M.Y. (2008). Induction of p27(kipl) by 2,4,3'5'-tetramethoxystilbene is regulated by protein phosphatase 2A-dependent Akt dephosphorylation in PC-3 prostate cancer cells. Arch Pharm Res 31,1187-1194.
Kong, M., Ditsworth, D., Lindsten, T., and Thompson, C.B. (2009). Alpha4 is an essential regulator of PP2A phosphatase activity. Mol Cell 36,51-60.
Kong, M., Fox, C.J., Mu, J., Solt, L., Xu, A., Cinalli, R.M., Birnbaum, M.J., Lindsten, T., and Thompson, C.B. (2004). The PP2A-associated protein alpha4 is an essential inhibitor of apoptosis. Science 306,695-698.
Kops, G.J., Dansen, T.B., Polderman, P.E., Saarloos, I., Wirtz, K.W., Coffer, P.J., Huang, T.T., Bos, J.L., Medema, R.H., and Burgering, B.M. (2002). Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419,316-321.
Kurimchak, A., and Grana, X. (2012). PP2A holoenzymes negatively and positively regulate cell cycle progression by dephosphorylating pocket proteins and multiple CDK substrates. Gene 499,1-7.
Laine, A., Come, C., Junttila, M.R., Puustinen, P., Niemela, M., Boulfroy, M., Thezenas, S., Darbon, J.M., Isola, J., Kallioniemi, O.P., et al. (2008). Involvement of CIP2A, a novel human oncoprotein inhibiting protein phosphatase 2A (PP2A), in breast cancer. Febs Journal 275,454-454.
Laine A, S.H., Come C, Rosenfeldt MT, Zwolinska A, Niemela M, Khanna A, Chan EK, Kahari VM, Kellokumpu-Lehtinen PL, Sansom OJ, Evan GI, Junttila MR, Ryan KM, Marine JC, Joensuu H, Westermarck J. (2013). Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1. Cancer Discov 3,182-197.
Li, C., Liang, Y.Y., Feng, X.H., Tsai, S.Y., Tsai, M.J., and O'Malley, B.W. (2008). Essential phosphatases and a phospho-degron are critical for regulation of SRC-3/AIB1 coactivator function and turnover. Mol Cell 31,835-849.
Li, H.H., Cai, X., Shouse, GP., Piluso, L.G., and Liu, X. (2007). A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55. EMBO J 26,402-411.
Liao, Y., and Hung, M.C. (2004). A new role of protein phosphatase 2a in adenoviral El A protein-mediated sensitization to anticancer drug-induced apoptosis in human breast cancer cells. Cancer Res 64,5938-5942.
Liu, J., and Sidell, N. (2005). Anti-estrogenic effects of conjugated linoleic acid through modulation of estrogen receptor phosphorylation. Breast Cancer Res Treat 94, 161-169.
Lu, Q., Surks, H.K., Ebling, H., Baur, W.E., Brown, D., Pallas, D.C., and Karas, R.H. (2003). Regulation of estrogen receptor alpha-mediated transcription by a direct interaction with protein phosphatase 2A. J Biol Chem 278,4639-4645.
Ma, L., Wen, Z.S., Liu, Z., Hu, Z., Ma, J., Chen, X.Q., Liu, Y.Q., Pu, J.X., Xiao, W.L., Sun, H.D., et al. (2013). Overexpression and small molecule-triggered downregulation of CIP2A in lung cancer. PLoS One 6, e20159.
Modak, C., and Bryant, P. (2008). Casein Kinase I epsilon positively regulates the Akt pathway in breast cancer cell lines. Biochem Biophys Res Commun 368,801-807.
Murata, K., Wu, J., and Brautigan, D.L. (1997). B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc Natl Acad Sci U S A 94,10624-10629.
Nahta, R., Yu, D., Hung, M.C., Hortobagyi, G.N., and Esteva, F.J. (2006). Mechanisms of disease:understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol 3,269-280.
Niemela, M., Kauko, O., Sihto, H., Mpindi, J.P., Nicorici, D., Pernila, P., Kallioniemi, O.P., Joensuu, H., Hautaniemi, S., and Westermarck, J. (2012). CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes. Oncogene 31,4266-4278.
Polyak, K., and Vogt, P.K. (2012). Progress in breast cancer research. Proc Natl Acad Sci U S A 109,2715-2717.
Ruediger, R., Pham, H.T., and Walter, G. (2001). Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the A alpha subunit gene. Oncogene 20,10-15.
Ruediger, R., Ruiz, J., and Walter, G. (2011). Human cancer-associated mutations in the Aalpha subunit of protein phosphatase 2A increase lung cancer incidence in Aalpha knock-in and knockout mice. Mol Cell Biol 31,3832-3844.
Sablina, A.A., Chen, W., Arroyo, J.D., Corral, L., Hector, M., Bulmer, S.E., DeCaprio, J.A., and Hahn, W.C. (2007). The tumor suppressor PP2A Abeta regulates the RalA GTPase. Cell 129,969-982.
Sents, W., Ivanova, E., Lambrecht, C., Haesen, D., and Janssens, V. (2012). The biogenesis of active protein phosphatase 2A holoenzymes:a tightly regulated process creating phosphatase specificity. FEBS J 280,644-661.
Seshacharyulu, P., Pandey, P., Datta, K., and Batra, S.K. (2013). Phosphatase:PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Lett, (in press)
Su, J.L., Cheng, X., Yamaguchi, H., Chang, Y.W., Hou, C.F., Lee, D.F., Ko, H.W., Hua, K.T., Wang, Y.N., Hsiao, M., et al. (2011). FOXO3a-Dependent Mechanism of ElA-Induced Chemosensitization. Cancer Res 71,6878-6887.
Suzuki, K., Chikamatsu, Y., and Takahashi, K. (2005). Requirement of protein phosphatase 2A for recruitment of IQGAP1 to Rac-bound betal integrin. J Cell Physiol 203,487-492.
Suzuki, K., and Takahashi, K. (2006). Induction of E-cadherin endocytosis by loss of protein phosphatase 2A expression in human breast cancers. Biochem Biophys Res Commun 349,255-260.
Takahashi, K., Nakajima, E., and Suzuki, K. (2006). Involvement of protein phosphatase 2A in the maintenance of E-cadherin-mediated cell-cell adhesion through recruitment of IQGAP1. J Cell Physiol 206,814-820.
Tan, B., Long, X., Nakshatri, H., Nephew, K.P., and Bigsby, R.M. (2008). Striatin-3 gamma inhibits estrogen receptor activity by recruiting a protein phosphatase. J Mol Endocrinol 40,199-210.
Tseng LM, L.C., Chang KC, Chu PY, Shiau CW, Chen KF. (2012). CIP2A is a target of bortezomib in human triple negative breast cancer cells. Breast Cancer Res 14, R68.
Vinayak, S., and Carlson, R.W. (2013). mTOR inhibitors in the treatment of breast cancer. Oncology (Williston Park) 27,38-44,46,48 passim.
Woo, M.M., Salamanca, C.M., Symowicz, J., Stack, M.S., Miller, D.M., Leung, P.C., Gilks, C.B., and Auersperg, N. (2008). SV40 early genes induce neoplastic properties in serous borderline ovarian tumor cells. Gynecol Oncol.
Xu, J., Chen, Y, and Olopade, O.I. (2010). MYC and Breast Cancer. Genes Cancer 1, 629-640.
Yang, W.H., Lan, H.Y., Huang, C.H., Tai, S.K., Tzeng, C.H., Kao, S.Y., Wu, K.J., Hung, M.C., and Yang, M.H. (2012). RAC1 activation mediates Twist1-induced cancer cell migration. Nat Cell Biol 14,366-374.
Yu, H.C., Chen, H.J., Chang, Y.L., Liu, C.Y., Shiau, C.W., Cheng, A.L., and Chen, K.F. (2013). Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma. Biochem Pharmacol 85,356-366.
Zeisberg, M., and Neilson, E.G (2009). Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119,1429-1437.
Zhou, J., Pham, H.T., Ruediger, R., and Walter, G. (2003). Characterization of the Aalpha and Abeta subunit isoforms of protein phosphatase 2A:differences in expression, subunit interaction, and evolution. Biochem J 369,387-398.
Aranda-Orgilles, B., Aigner, J., Kunath, M., Lurz, R., Schneider, R., and Schweiger, S. (2008). Active transport of the ubiquitin ligase MIDI along the microtubules is regulated by protein phosphatase 2A. PLoS One 3, e3507.
Aranda-Orgilles, B., Rutschow, D., Zeller, R., Karagiannidis, A.I., Kohler, A., Chen, C, Wilson, T., Krause, S., Roepcke, S., Lilley, D., et al. (2011). Protein phosphatase 2A (PP2A)-specific ubiquitin ligase MID1 is a sequence-dependent regulator of translation efficiency controlling 3-phosphoinositide-dependent protein kinase-1 (PDPK-1). J Biol Chem 286,39945-39957.
Arnold, H.K., and Sears, R.C. (2006). Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation. Mol Cell Biol 26,2832-2844.
Arroyo, J.D., and Hahn, W.C. (2005). Involvement of PP2A in viral and cellular transformation. Oncogene 24,7746-7755.
Basu, S. (2011). PP2A in the regulation of cell motility and invasion. Curr Protein Pept Sci 12,3-11.
Bradford, M.M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72,248-254.
Calin, G.A., di Iasio, M.G., Caprini, E., Vorechovsky, I., Natali, P.G., Sozzi, G, Croce, C.M., Barbanti-Brodano, G, Russo, G, and Negrini, M. (2000). Low frequency of alterations of the alpha (PPP2R1A) and beta (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene 19, 1191-1195.
Campos, A., and Vasconcelos, V. (2010). Molecular mechanisms of microcystin toxicity in animal cells. Int J Mol Sci 11,268-287.
Chalfant, C.E., Szulc, Z., Roddy, P., Bielawska, A., and Hannun, Y.A. (2004). The structural requirements for ceramide activation of serine-threonine protein phosphatases. J Lipid Res 45,496-506.
Chang, L., and Goldman, R.D. (2004). Intermediate filaments mediate cytoskeletal crosstalk. Nat Rev Mol Cell Biol 5,601-613.
Chen, D.N., Zeng, J., Wang, F., Zheng, W., Tu, W.W., Zhao, J.S., and Xu, J. (2012). Hyperphosphorylation of intermediate filament proteins is involved in microcystin-LR-induced toxicity in HL7702 cells. Toxicol Lett 214,192-199.
Chen, J., Xie, P., Li, L., and Xu, J. (2009). First identification of the hepatotoxic microcystins in the serum of a chronically exposed human population together with indication of hepatocellular damage. Toxicol Sci 108,81-89.
Chen, L., Zhang, X., Zhou, W., Qiao, Q., Liang, H., Li, G., Wang, J., and Cai, F. (2013). The interactive effects of cytoskeleton disruption and mitochondria dysfunction lead to reproductive toxicity induced by microcystin-LR. PLoS One 8, e53949.
Chen LP, L.Y., Li DC, Zhu XN, Yang P, Li WX, Zhu W, Zhao J, Li XD, Xiao YM, Zhang Y, Xing XM, Wang Q, Zhang B, Lin YC, Zeng JL, Zhang SX, Liu CX, Li ZF, Zeng XW, Lin ZN, Zhuang ZX, Chen W. (2011). a4 is highly expressed in carcinogen-transformed human cells and primary human cancers. Oncogene 30, 2943-2953.
Chen, T., Wang, Q., Cui, J., Yang, W., Shi, Q., Hua, Z., Ji, J., and Shen, P. (2005). Induction of apoptosis in mouse liver by microcystin-LR:a combined transcriptomic, proteomic, and simulation strategy. Mol Cell Proteomics 4, 958-974.
Cho, U.S., and Xu, W. (2007). Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 445,53-57.
Codd, G.A., Morrison, L.F., and Metcalf, J.S. (2005). Cyanobacterial toxins:risk management for health protection. Toxicol Appl Pharmacol 203,264-272.
Coll, J.L., Ben-Ze'ev, A., Ezzell, R.M., Rodriguez Fernandez, J.L., Baribault, H., Oshima, R.G, and Adamson, E.D. (1995). Targeted disruption of vinculin genes in F9 and embryonic stem cells changes cell morphology, adhesion, and locomotion. Proc Natl Acad Sci U S A 92,9161-9165.
Dawson, R.M. (1998). The toxicology of microcystins. Toxicon 36,953-962.
Delgado, L.F., Charles, P., Glucina, K., and Morlay, C. (2012). The removal of endocrine disrupting compounds, pharmaceutically activated compounds and cyanobacterial toxins during drinking water preparation using activated carbon--a review. Sci Total Environ 435-436,509-525.
Dias, E., Andrade, M., Alverca, E., Pereira, P., Batoreu, M.C., Jordan, P., and Silva, M.J. (2009). Comparative study of the cytotoxic effect of microcistin-LR and purified extracts from Microcystis aeruginosa on a kidney cell line. Toxicon 53,487-495.
Ding, W.X., Shen, H.M., and Ong, C.N. (2000a). Critical role of reactive oxygen species and mitochondrial permeability transition in microcystin-induced rapid apoptosis in rat hepatocytes. Hepatology 32,547-555.
Ding, W.X., Shen, H.M., and Ong, C.N. (2000b). Microcystic cyanobacteria extract induces cytoskeletal disruption and intracellular glutathione alteration in hepatocytes. Environ Health Perspect 108,605-609.
Ding, W.X., Shen, H.M., and Ong, C.N. (2001). Critical role of reactive oxygen species formation in microcystin-induced cytoskeleton disruption in primary cultured hepatocytes. J Toxicol Environ Health A 64,507-519.
Dobrowsky, R.T., Kamibayashi, C., Mumby, M.C., and Hannun, Y.A. (1993). Ceramide activates heterotrimeric protein phosphatase 2A. J Biol Chem 268,15523-15530.
Eichhorn, P.J., Creyghton, M.P., and Bernards, R. (2009). Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta 1795,1-15.
Embade, N., Valeron, P.F., Aznar, S., Lopez-Collazo, E., and Lacal, J.C. (2000). Apoptosis induced by Rac GTPase correlates with induction of FasL and ceramides production. Mol Biol Cell 11,4347-4358.
Etienne-Manneville, S., and Hall, A. (2002). Rho GTPases in cell biology. Nature 420, 629-635.
Ferrao-Filho Ada, S., Kozlowsky-Suzuki, B., and Azevedo, S.M. (2002). Accumulation of microcystins by a tropical zooplankton community. Aquat Toxicol 59,201-208.
Feurstein, D., Holst, K., Fischer, A., and Dietrich, D.R. (2009). Oatp-associated uptake and toxicity of microcystins in primary murine whole brain cells. Toxicol Appl Pharmacol 234,247-255.
Feurstein, D., Kleinteich, J., Heussner, A.H., Stemmer, K., and Dietrich, D.R. (2010). Investigation of microcystin congener-dependent uptake into primary murine neurons. Environ Health Perspect 118,1370-1375.
Fladmark, K.E., Brustugun, O.T., Hovland, R., Boe, R., Gjertsen, B.T., Zhivotovsky, B., and Doskeland, S.O. (1999). Ultrarapid caspase-3 dependent apoptosis induction by serine/threonine phosphatase inhibitors. Cell Death Differ 6,1099-1108.
Freeman, K.S. (2010). Harmful algal blooms. Musty warnings of toxicity. Environ Health Perspect 118, A473.
Frisch, S.M., and Screaton, R.A. (2001). Anoikis mechanisms. Curr Opin Cell Biol 13, 555-562.
Fu, W., Yu, Y., and Xu, L. (2009). Identification of temporal differentially expressed protein responses to microcystin in human amniotic epithelial cells. Chem Res Toxicol 22,41-51.
Fu, W.Y., Xu, L.H., and Yu, Y.N. (2005). Proteomic analysis of cellular response to microcystin in human amnion FL cells. J Proteome Res 4,2207-2215.
Fujiki, H., and Suganuma, M. (2011). Tumor promoters--microcystin-LR, nodularin and TNF-alpha and human cancer development. Anticancer Agents Med Chem 11, 4-18.
Galadari, S., Kishikawa, K., Kamibayashi, C., Mumby, M.C., and Hannun, Y.A. (1998). Purification and characterization of ceramide-activated protein phosphatases. Biochemistry 37,11232-11238.
Gehringer, M.M. (2004). Microcystin-LR and okadaic acid-induced cellular effects:a dualistic response. FEBS Lett 557,1-8.
Grossmann, J. (2002). Molecular mechanisms of "detachment-induced apoptosis--Anoikis". Apoptosis 7,247-260.
Hamm-Alvarez, S.F., Wei, X., Berndt, N., and Runnegar, M. (1996). Protein phosphatases independently regulate vesicle movement and microtubule subpopulations in hepatocytes. Am J Physiol 271, C929-943.
Hannun, Y.A., and Luberto, C. (2000). Ceramide in the eukaryotic stress response. Trends Cell Biol 10,73-80.
Hannun, Y.A., and Obeid, L.M. (1997). Ceramide and the eukaryotic stress response. Biochem Soc Trans 25,1171-1175.
Hannun, Y.A., and Obeid, L.M. (2008). Principles of bioactive lipid signalling:lessons from sphingolipids. Nat Rev Mol Cell Biol 9,139-150.
Honkanen, R.E., Zwiller, J., Moore, R.E., Daily, S.L., Khatra, B.S., Dukelow, M., and Boynton, A.L. (1990). Characterization of microcystin-LR, a potent inhibitor of type 1 and type 2A protein phosphatases. J Biol Chem 265,19401-19404.
Hou, Q., Jin, J., Zhou, H., Novgorodov, S.A., Bielawska, A., Szulc, Z.M., Hannun, Y.A., Obeid, L.M., and Hsu, Y.T. (2011). Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis. J Lipid Res 52,278-288.
Humphries, J.D., Wang, P., Streuli, C., Geiger, B., Humphries, M.J., and Ballestrem, C. (2007). Vinculin controls focal adhesion formation by direct interactions with talin and actin. J Cell Biol 179,1043-1057.
Inui, S., Sanjo, H., Maeda, K., Yamamoto, H., Miyamoto, E., and Sakaguchi, N. (1998). Ig receptor binding protein 1 (alpha4) is associated with a rapamycin-sensitive signal transduction in lymphocytes through direct binding to the catalytic subunit of protein phosphatase 2 A. Blood 92,539-546.
Janssens, V., and Goris, J. (2001). Protein phosphatase 2A:a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353,417-439.
Janssens, V., and Rebollo, A. (2012). The role and therapeutic potential of Ser/Thr phosphatase PP2A in apoptotic signalling networks in human cancer cells. Curr Mol Med 12,268-287.
Jochimsen, E.M., Carmichael, W.W., An, J.S., Cardo, D.M., Cookson, S.T., Holmes, C.E., Antunes, M.B., de Melo Filho, D.A., Lyra, T.M., Barreto, V.S., et al. (1998). Liver failure and death after exposure to microcystins at a hemodialysis center in Brazil. N Engl J Med 338,873-878.
Junttila, M.R., Li, S.P., and Westermarck, J. (2008). Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J 22, 954-965.
Junttila, M.R., Puustinen, P., Niemela, M., Ahola, R., Arnold, H., Bottzauw, T., Ala-aho, R., Nielsen, C., Ivaska, J., Taya, Y., et al. (2007). CIP2A inhibits PP2A in human malignancies. Cell 130,51-62.
Kim, B.C., and Kim, J.H. (1998). Exogenous C2-ceramide activates c-fos serum response element via Rac-dependent signalling pathway. Biochem J 330 (Pt 2), 1009-1014.
Klintworth, H., Newhouse, K., Li, T., Choi, W.S., Faigle, R., and Xia, Z. (2007). Activation of c-Jun N-terminal protein kinase is a common mechanism underlying paraquat- and rotenone-induced dopaminergic cell apoptosis. Toxicol Sci 97, 149-162.
Komatsu, M., Furukawa, T., Ikeda, R., Takumi, S., Nong, Q., Aoyama, K., Akiyama, S., Keppler, D., and Takeuchi, T. (2007). Involvement of mitogen-activated protein kinase signaling pathways in microcystin-LR-induced apoptosis after its selective uptake mediated by OATP1B1 and OATP1B3. Toxicol Sci 97,407-416.
Kong, M., Bui, T.V., Ditsworth, D., Gruber, J.J., Goncharov, D., Krymskaya, V.P., Lindsten, T., and Thompson, C.B. (2007). The PP2A-associated protein alpha4 plays a critical role in the regulation of cell spreading and migration. J Biol Chem 282,29712-29720.
Kong, M., Ditsworth, D., Lindsten, T., and Thompson, C.B. (2009). Alpha4 is an essential regulator of PP2A phosphatase activity. Mol Cell 36,51-60.
Kong, M., Fox, C.J., Mu, J., Solt, L., Xu, A., Cinalli, R.M., Birnbaum, M.J., Lindsten, T., and Thompson, C.B. (2004). The PP2A-associated protein alpha4 is an essential inhibitor of apoptosis. Science 306,695-698.
Laine, A., Come, C., Junttila, M.R., Puustinen, P., Niemela, M., Boulfroy, M., Thezenas, S., Darbon, J.M., Isola, J., Kallioniemi, O.P., et al. (2008). Involvement of CIP2A, a novel human oncoprotein inhibiting protein phosphatase 2A (PP2A), in breast cancer. Febs Journal 275,454-454.
Laine A, S.H., Come C, Rosenfeldt MT, Zwolinska A, Niemela M, Khanna A, Chan EK, Kahari VM, Kellokumpu-Lehtinen PL, Sansom OJ, Evan GI, Junttila MR, Ryan KM, Marine JC, Joensuu H, Westermarck J. (2013). Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1. Cancer Discov 3,182-197.
Lezcano, N., Sedan, D., Lucotti, I., Giannuzzi, L., Vittone, L., Andrinolo, D., and Mundina-Weilenmann, C. (2012). Subchronic microcystin-LR exposure increased hepatic apoptosis and induced compensatory mechanisms in mice. J Biochem Mol Toxicol 26,131-138.
Li, G, Cai, F., Yan, W., Li, C., and Wang, J. (2012a). A proteomic analysis of MCLR-induced neurotoxicity:implications for Alzheimer's disease. Toxicol Sci 127,485-495.
Li, T., Huang, P., Liang, J., Fu, W., Guo, Z., and Xu, L. (2011a). Microcystin-LR (MCLR) Induces a Compensation of PP2A Activity Mediated by alpha4 Protein in HEK293 Cells. Int J Biol Sci 7,740-752.
Li, T., Ting, L., Wang, H., Li, N., Fu, ., Guo, Z., and Xu, L. (2012b). Microcystin-LR induces ceramide to regulate PP2A and destabilize cytoskeleton in HEK293 cells. Toxicol Sci 128,147-157.
Li, Y., Chen, J.A., Zhao, Q., Pu, C., Qiu, Z., Zhang, R., and Shu, W. (2011b). A cross-sectional investigation of chronic exposure to microcystin in relationship to childhood liver damage in the Three Gorges Reservoir Region, China. Environ Health Perspect 119,1483-1488.
Lin, S.S., Bassik, M.C., Suh, H., Nishino, M., Arroyo, J.D., Hahn, W.C., Korsmeyer, S.J., and Roberts, T.M. (2006). PP2A regulates BCL-2 phosphorylation and proteasome-mediated degradation at the endoplasmic reticulum. J Biol Chem 281, 23003-23012.
Lowe, M., Gonatas, N.K., and Warren, G (2000). The mitotic phosphorylation cycle of the cis-Golgi matrix protein GM130. J Cell Biol 149,341-356.
MacKintosh, C., Beattie, K.A., Klumpp, S., Cohen, P., and Codd, G.A. (1990). Cyanobacterial microcystin-LR is a potent and specific inhibitor of protein phosphatases 1 and 2A from both mammals and higher plants. FEBS Lett 264, 187-192.
McConnell, J.L., Gomez, R.J., McCorvey, L.R., Law, B.K., and Wadzinski, B.E. (2007). Identification of a PP2A-interacting protein that functions as a negative regulator of phosphatase activity in the ATM/ATR signaling pathway. Oncogene 26,6021-6030.
McConnell, J.L., Watkins, G.R., Soss, S.E., Franz, H.S., McCorvey, L.R., Spiller, B.W., Chazin, W.J., and Wadzinski, B.E. (2010). Alpha4 is a ubiquitin-binding protein that regulates protein serine/threonine phosphatase 2A ubiquitination. Biochemistry 49,1713-1718.
Meng, G, Sun, Y., Fu, W., Guo, Z., and Xu, L. (2011). Microcystin-LR induces cytoskeleton system reorganization through hyperphosphorylation of tau and HSP27 via PP2A inhibition and subsequent activation of the p38 MAPK signaling pathway in neuroendocrine (PC 12) cells. Toxicology 290,218-229.
Mukhopadhyay, A., Saddoughi, S.A., Song, P., Sultan, I., Ponnusamy, S., Senkal, C.E., Snook, C.F., Arnold, H.K., Sears, R.C., Hannun, Y.A., et al. (2009). Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2 A activity and signaling. FASEB J 23,751-763.
Mumby, M. (2007). PP2A:unveiling a reluctant tumor suppressor. Cell 130,21-24.
Murata, K., Wu, J., and Brautigan, D.L. (1997). B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc Natl Acad Sci U S A 94,10624-10629.
Nagendra, D.C., Burke, J.,3rd, Maxwell, GL., and Risinger, J.I. (2012). PPP2R1A mutations are common in the serous type of endometrial cancer. Mol Carcinog 51, 826-831.
Nanahoshi, M., Tsujishita, Y., Tokunaga, C., Inui, S., Sakaguchi, N., Hara, K., and Yonezawa, K. (1999). Alpha4 protein as a common regulator of type 2A-related serine/threonine protein phosphatases. FEBS Lett 446,108-112.
Niemela, M., Kauko, O., Sihto, H., Mpindi, J.P., Nicorici, D., Pernila, P., Kallioniemi, O.P., Joensuu, H., Hautaniemi, S., and Westermarck, J. (2012). CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes. Oncogene 31,4266-4278.
Oberhammer, F.A., Hochegger, K., Froschl, G., Tiefenbacher, R., and Pavelka, M. (1994). Chromatin condensation during apoptosis is accompanied by degradation of lamin A+B, without enhanced activation of cdc2 kinase. J Cell Biol 126, 827-837.
Ohta, T., Nishiwaki, R., Yatsunami, J., Komori, A., Suganuma, M., and Fujiki, H. (1992). Hyperphosphorylation of cytokeratins 8 and 18 by microcystin-LR, a new liver tumor promoter, in primary cultured rat hepatocytes. Carcinogenesis 13, 2443-2447.
Prendergast, G.C. (1999). Mechanisms of apoptosis by c-Myc. Oncogene 18, 2967-2987.
Prickett, T.D., and Brautigan, D.L. (2007). Cytokine activation of p38 mitogen-activated protein kinase and apoptosis is opposed by alpha-4 targeting of protein phosphatase 2A for site-specific dephosphorylation of MEK3. Mol Cell Biol 27,4217-4227.
Ruediger, R., Pham, H.T., and Walter, G. (2001). Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the A alpha subunit gene. Oncogene 20,10-15.
Runnegar, M., Berndt, N., Kong, S.M., Lee, E.Y., and Zhang, L. (1995). In vivo and in vitro binding of microcystin to protein phosphatases 1 and 2A. Biochem Biophys Res Commun 216,162-169.
Ruvolo, P.P., Clark, W., Mumby, M., Gao, F., and May, W.S. (2002). A functional role for the B56 alpha-subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2 phosphorylation status and function. J Biol Chem 277, 22847-22852.
Saddoughi, S.A., Gencer, S., Peterson, Y.K., Ward, K.E., Mukhopadhyay, A., Oaks, J., Bielawski, J., Szulc, Z.M., Thomas, R.J., Selvam, S.P., et al. (2013). Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Mol Med 5, 105-121.
Saito, T., Okano, K., Park, H.D., Itayama, T., Inamori, Y, Neilan, B.A., Burns, B.P., and Sugiura, N. (2003). Detection and sequencing of the microcystin LR-degrading gene, mlrA, from new bacteria isolated from Japanese lakes. FEMS Microbiol Lett 229,271-276.
Sents, W., Ivanova, E., Lambrecht, C., Haesen, D., and Janssens, V. (2012). The biogenesis of active protein phosphatase 2A holoenzymes:a tightly regulated process creating phosphatase specificity. FEBS J 280,644-661.
Seshacharyulu, P., Pandey, P., Datta, K., and Batra, S.K. (2013). Phosphatase:PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Lett.
Sontag, E. (2001). Protein phosphatase 2A:the Trojan Horse of cellular signaling. Cell Signal 13,7-16.
Sun, Y, Meng, G.M., Guo, Z.L., and Xu, L.H. (2011). Regulation of heat shock protein 27 phosphorylation during microcystin-LR-induced cytoskeletal reorganization in a human liver cell line. Toxicol Lett 207,270-277.
Tamaki, M., Goi, T., Hirono, Y., Katayama, K., and Yamaguchi, A. (2004). PPP2R1B gene alterations inhibit interaction of PP2A-Abeta and PP2A-C proteins in colorectal cancers. Oncol Rep 11,655-659.
Trockenbacher, A., Suckow, V., Foerster, J., Winter, J., Krauss, S., Ropers, H.H., Schneider, R., and Schweiger, S. (2001). MIDI, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nat Genet 29,287-294.
Tsuji, K., Naito, S., Kondo, F., Ishikawa, N., Watanabe, M.F., Suzuki, M., and Harada, K. (1994). Stability of microcystins from cyanobacteria:effect of light on decomposition and isomerization. Environ Sci Technol 28,173-177.
Turowski, P., Myles, T., Hemmings, B.A., Fernandez, A., and Lamb, N.J. (1999). Vimentin dephosphorylation by protein phosphatase 2A is modulated by the targeting subunit B55. Mol Biol Cell 10,1997-2015.
Van Hoof, C., and Goris, J. (2003). Phosphatases in apoptosis:to be or not to be, PP2A is in the heart of the question. Biochim Biophys Acta 1640,97-104.
Wang, M., Chan, L.L., Si, M., Hong, H., and Wang, D. (2010). Proteomic analysis of hepatic tissue of zebrafish (Danio rerio) experimentally exposed to chronic microcystin-LR. Toxicol Sci 113,60-69.
Wang, N., Leung, H.T., Mazalouskas, M.D., Watkins, G.R., Gomez, R.J., and Wadzinski, B.E. (2012). Essential roles of the Tap42-regulated protein phosphatase 2A (PP2A) family in wing imaginal disc development of Drosophila melanogaster. PLoS One 7, e38569.
Weng, D., Lu, Y, Wei, Y, Liu, Y, and Shen, P. (2007). The role of ROS in microcystin-LR-induced hepatocyte apoptosis and liver injury in mice. Toxicology 232,15-23.
Widau, R.C., Jin, Y, Dixon, S.A., Wadzinski, B.E., and Gallagher, P.J. (2010). Protein phosphatase 2A (PP2A) holoenzymes regulate death-associated protein kinase (DAPK) in ceramide-induced anoikis. J Biol Chem 285,13827-13838.
Xia, Z., Dickens, M., Raingeaud, J., Davis, R.J., and Greenberg, M.E. (1995). Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270,1326-1331.
Xie, L., Xie, P., Guo, L., Li, L., Miyabara, Y, and Park, H.D. (2005). Organ distribution and bioaccumulation of microcystins in freshwater fish at different trophic levels from the eutrophic Lake Chaohu, China. Environ Toxicol 20,293-300.
Xing, Y, Li, Z., Chen, Y, Stock, J.B., Jeffrey, P.D., and Shi, Y (2008). Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell 133, 154-163.
Xing, Y, Xu, Y, Chen, Y., Jeffrey, P.D., Chao, Y, Lin, Z., Li, Z., Strack, S., Stock, J.B., and Shi, Y (2006). Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell 127,341-353.
Yoo, S.J., Jimenez, R.H., Sanders, J.A., Boylan, J.M., Brautigan, D.L., and Gruppuso, P.A. (2008). The alpha4-containing form of protein phosphatase 2A in liver and hepatic cells. J Cell Biochem 105,290-300.
Yuan, M., Carmichael, W.W., and Hilborn, E.D. (2006). Microcystin analysis in human sera and liver from human fatalities in Caruaru, Brazil 1996. Toxicon 48,627-640.
Zegura, B., Straser, A., and Filipic, M. (2011). Genotoxicity and potential carcinogenicity of cyanobacterial toxins-a review. Mutat Res 727,16-41.
Zeidan, Y.H., and Hannun, Y.A. (2010). The acid sphingomyelinase/ceramide pathway: biomedical significance and mechanisms of regulation. Curr Mol Med 10,454-466.
Zeidan, Y.H., Jenkins, R.W., and Hannun, Y.A. (2008). Remodeling of cellular cytoskeleton by the acid sphingomyelinase/ceramide pathway. J Cell Biol 181, 335-350.
Zhang, X.X., Fu, Z., Zhang, Z., Miao, C., Xu, P., Wang, T., Yang, L., and Cheng, S. (2012). Microcystin-LR promotes melanoma cell invasion and enhances matrix metalloproteinase-2/-9 expression mediated by NF-kappaB activation. Environ Sci Technol 46,11319-11326.
Zhao, Y, Xie, P., and Fan, H. (2011). Genomic profiling of microRNAs and proteomics reveals an early molecular alteration associated with tumorigenesis induced by MC-LR in mice. Environ Sci Technol 46,34-41.
Zhou, J., Pham, H.T., Ruediger, R., and Walter, G. (2003). Characterization of the Aalpha and Abeta subunit isoforms of protein phosphatase 2A:differences in expression, subunit interaction, and evolution. Biochem J 369,387-398.
Zhu, Y., Zhong, X., Zheng, S., Ge, Z., Du, Q., and Zhang, S. (2005). Transformation of immortalized colorectal crypt cells by microcystin involving constitutive activation of Akt and MAPK cascade. Carcinogenesis 26,1207-1214.
Alayev, A., and Holz, M.K. (2013). mTOR signaling for biological control and cancer. J Cell Physiol.
Arnold, H.K., and Sears, R.C. (2006). Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation. Mol Cell Biol 26,2832-2844.
Baysal, B.E., Willett-Brozick, J.E., Taschner, P.E., Dauwerse, J.G., Devilee, P., and Devlin, B. (2001). A high-resolution integrated map spanning the SDHD gene at 11q23:a 1.1-Mb BAC contig, a partial transcript map and 15 new repeat polymorphisms in a tumour-suppressor region. Eur J Hum Genet 9,121-129.
Bradbury, P., Mahmassani, M., Zhong, J., Turner, K., Paul, A., Verrills, N.M., and O'Neill, G.M. (2012). PP2A phosphatase suppresses function of the mesenchymal invasion regulator NEDD9. Biochim Biophys Acta 1823,290-297.
Calin, G.A., di Iasio, M.G., Caprini, E., Vorechovsky, I., Natali, P.G., Sozzi, G, Croce, C.M., Barbanti-Brodano, G, Russo, G, and Negrini, M. (2000). Low frequency of alterations of the alpha (PPP2R1A) and beta (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene 19, 1191-1195.
Chen LP, L.Y., Li DC, Zhu XN, Yang P, Li WX, Zhu W, Zhao J, Li XD, Xiao YM, Zhang Y, Xing XM, Wang Q, Zhang B, Lin YC, Zeng JL, Zhang SX, Liu CX, Li ZF, Zeng XW, Lin ZN, Zhuang ZX, Chen W. (2011). a4 is highly expressed in carcinogen-transformed human cells and primary human cancers. Oncogene 30, 2943-2953.
Chen, W., Arroyo, J.D., Timmons, J.C., Possemato, R., and Hahn, W.C. (2005). Cancer-associated PP2A Aalpha subunits induce functional haploinsufficiency and tumorigenicity. Cancer Res 65,8183-8192.
Chen, W., Possemato, R., Campbell, K.T., Plattner, C.A., Pallas, D.C., and Hahn, W.C. (2004). Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell 5,127-136.
Cho, U.S., and Xu, W. (2007). Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 445,53-57.
Come C, L.A., Chanrion M, Edgren H, Mattila E, Liu X, Jonkers J, Ivaska J, Isola J, Darbon JM, Kallioniemi O, Thezenas S, Westermarck J. (2009). CIP2A Is Associated with Human Breast Cancer Aggressivity. Clin Cancer Res 15, 5092-5100.
Dupont, W.D., Breyer, J.P., Bradley, K.M., Schuyler, P.A., Plummer, W.D., Sanders, M.E., Page, D.L., and Smith, J.R. (2010). Protein phosphatase 2A subunit gene haplotypes and proliferative breast disease modify breast cancer risk. Cancer 116, 8-19.
Eichhorn, P.J., Creyghton, M.P., and Bernards, R. (2009). Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta 1795,1-15.
Esplin, E.D., Ramos, P., Martinez, B., Tomlinson, G.E., Mumby, M.C., and Evans, GA. (2006). The glycine 90 to aspartate alteration in the Abeta subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function. Genes Chromosomes Cancer 45,182-190.
Fisher, B., Costantino, J.P., Wickerham, D.L., Redmond, C.K., Kavanah, M., Cronin, W.M., Vogel, V., Robidoux, A., Dimitrov, N., Atkins, J., et al. (1998). Tamoxifen for prevention of breast cancer:report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90,1371-1388.
Fu, W., Yu, Y., and Xu, L. (2009). Identification of temporal differentially expressed protein responses to microcystin in human amniotic epithelial cells. Chem Res Toxicol 22,41-51.
Fu, W.Y., Xu, L.H., and Yu, Y.N. (2005). Proteomic analysis of cellular response to microcystin in human amnion FL cells. J Proteome Res 4,2207-2215.
Gopalakrishna, R., Gundimeda, U., Fontana, J.A., and Clarke, R. (1999). Differential distribution of protein phosphatase 2 A in human breast carcinoma cell lines and its relation to estrogen receptor status. Cancer Lett 136,143-151.
Huang, P., Zheng, Y.F., and Xu, L.H. (2008). Oral administration of cyanobacterial bloom extract induced the altered expression of the PP2A, Bax, and Bcl-2 in mice. Environ Toxicol.
Hui, L., Rodrik, V., Pielak, R.M., Knirr, S., Zheng, Y, and Foster, D.A. (2005). mTOR-dependent suppression of protein phosphatase 2A is critical for phospholipase D survival signals in human breast cancer cells. J Biol Chem 280, 35829-35835.
Janssens, V., and Goris, J. (2001). Protein phosphatase 2A:a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353,417-439.
Janssens, V., and Rebollo, A. (2012). The role and therapeutic potential of Ser/Thr phosphatase PP2A in apoptotic signalling networks in human cancer cells. Curr Mol Med 12,268-287.
Junttila, M.R., Puustinen, P., Niemela, M., Ahola, R., Arnold, H., Bottzauw, T., Ala-aho, R., Nielsen, C., Ivaska, J., Taya, Y., et al. (2007). CIP2A inhibits PP2A in human malignancies. Cell 130,51-62.
Keen, J.C., Garrett-Mayer, E., Pettit, C., Mack, K.M., Manning, J., Herman, J.G., and Davidson, N.E. (2004). Epigenetic regulation of protein phosphatase 2A (PP2A), lymphotactin (XCL1) and estrogen receptor alpha (ER) expression in human breast cancer cells. Cancer Biol Ther 3,1304-1312.
Keen, J.C., Zhou, Q., Park, B.H., Pettit, C., Mack, K.M., Blair, B., Brenner, K., and Davidson, N.E. (2005). Protein phosphatase 2A regulates estrogen receptor alpha (ER) expression through modulation of ER mRNA stability. J Biol Chem 280, 29519-29524.
Kim, S.W., Jung, H.K., and Kim, M.Y. (2008). Induction of p27(kipl) by 2,4,3'5'-tetramethoxystilbene is regulated by protein phosphatase 2A-dependent Akt dephosphorylation in PC-3 prostate cancer cells. Arch Pharm Res 31,1187-1194.
Kong, M., Ditsworth, D., Lindsten, T., and Thompson, C.B. (2009). Alpha4 is an essential regulator of PP2A phosphatase activity. Mol Cell 36,51-60.
Kong, M., Fox, C.J., Mu, J., Solt, L., Xu, A., Cinalli, R.M., Birnbaum, M.J., Lindsten, T., and Thompson, C.B. (2004). The PP2A-associated protein alpha4 is an essential inhibitor of apoptosis. Science 306,695-698.
Kops, G.J., Dansen, T.B., Polderman, P.E., Saarloos, I., Wirtz, K.W., Coffer, P.J., Huang, T.T., Bos, J.L., Medema, R.H., and Burgering, B.M. (2002). Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419,316-321.
Kurimchak, A., and Grana, X. (2012). PP2A holoenzymes negatively and positively regulate cell cycle progression by dephosphorylating pocket proteins and multiple CDK substrates. Gene 499,1-7.
Laine, A., Come, C., Junttila, M.R., Puustinen, P., Niemela, M., Boulfroy, M., Thezenas, S., Darbon, J.M., Isola, J., Kallioniemi, O.P., et al. (2008). Involvement of CIP2A, a novel human oncoprotein inhibiting protein phosphatase 2A (PP2A), in breast cancer. Febs Journal 275,454-454.
Laine A, S.H., Come C, Rosenfeldt MT, Zwolinska A, Niemela M, Khanna A, Chan EK, Kahari VM, Kellokumpu-Lehtinen PL, Sansom OJ, Evan GI, Junttila MR, Ryan KM, Marine JC, Joensuu H, Westermarck J. (2013). Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1. Cancer Discov 3,182-197.
Li, C., Liang, Y.Y., Feng, X.H., Tsai, S.Y., Tsai, M.J., and O'Malley, B.W. (2008). Essential phosphatases and a phospho-degron are critical for regulation of SRC-3/AIB1 coactivator function and turnover. Mol Cell 31,835-849.
Li, H.H., Cai, X., Shouse, GP., Piluso, L.G., and Liu, X. (2007). A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55. EMBO J 26,402-411.
Liao, Y., and Hung, M.C. (2004). A new role of protein phosphatase 2a in adenoviral El A protein-mediated sensitization to anticancer drug-induced apoptosis in human breast cancer cells. Cancer Res 64,5938-5942.
Liu, J., and Sidell, N. (2005). Anti-estrogenic effects of conjugated linoleic acid through modulation of estrogen receptor phosphorylation. Breast Cancer Res Treat 94, 161-169.
Lu, Q., Surks, H.K., Ebling, H., Baur, W.E., Brown, D., Pallas, D.C., and Karas, R.H. (2003). Regulation of estrogen receptor alpha-mediated transcription by a direct interaction with protein phosphatase 2A. J Biol Chem 278,4639-4645.
Ma, L., Wen, Z.S., Liu, Z., Hu, Z., Ma, J., Chen, X.Q., Liu, Y.Q., Pu, J.X., Xiao, W.L., Sun, H.D., et al. (2013). Overexpression and small molecule-triggered downregulation of CIP2A in lung cancer. PLoS One 6, e20159.
Modak, C., and Bryant, P. (2008). Casein Kinase I epsilon positively regulates the Akt pathway in breast cancer cell lines. Biochem Biophys Res Commun 368,801-807.
Murata, K., Wu, J., and Brautigan, D.L. (1997). B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc Natl Acad Sci U S A 94,10624-10629.
Nahta, R., Yu, D., Hung, M.C., Hortobagyi, G.N., and Esteva, F.J. (2006). Mechanisms of disease:understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol 3,269-280.
Niemela, M., Kauko, O., Sihto, H., Mpindi, J.P., Nicorici, D., Pernila, P., Kallioniemi, O.P., Joensuu, H., Hautaniemi, S., and Westermarck, J. (2012). CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes. Oncogene 31,4266-4278.
Polyak, K., and Vogt, P.K. (2012). Progress in breast cancer research. Proc Natl Acad Sci U S A 109,2715-2717.
Ruediger, R., Pham, H.T., and Walter, G. (2001). Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the A alpha subunit gene. Oncogene 20,10-15.
Ruediger, R., Ruiz, J., and Walter, G. (2011). Human cancer-associated mutations in the Aalpha subunit of protein phosphatase 2A increase lung cancer incidence in Aalpha knock-in and knockout mice. Mol Cell Biol 31,3832-3844.
Sablina, A.A., Chen, W., Arroyo, J.D., Corral, L., Hector, M., Bulmer, S.E., DeCaprio, J.A., and Hahn, W.C. (2007). The tumor suppressor PP2A Abeta regulates the RalA GTPase. Cell 129,969-982.
Sents, W., Ivanova, E., Lambrecht, C., Haesen, D., and Janssens, V. (2012). The biogenesis of active protein phosphatase 2A holoenzymes:a tightly regulated process creating phosphatase specificity. FEBS J 280,644-661.
Seshacharyulu, P., Pandey, P., Datta, K., and Batra, S.K. (2013). Phosphatase:PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Lett, (in press)
Su, J.L., Cheng, X., Yamaguchi, H., Chang, Y.W., Hou, C.F., Lee, D.F., Ko, H.W., Hua, K.T., Wang, Y.N., Hsiao, M., et al. (2011). FOXO3a-Dependent Mechanism of ElA-Induced Chemosensitization. Cancer Res 71,6878-6887.
Suzuki, K., Chikamatsu, Y., and Takahashi, K. (2005). Requirement of protein phosphatase 2A for recruitment of IQGAP1 to Rac-bound betal integrin. J Cell Physiol 203,487-492.
Suzuki, K., and Takahashi, K. (2006). Induction of E-cadherin endocytosis by loss of protein phosphatase 2A expression in human breast cancers. Biochem Biophys Res Commun 349,255-260.
Takahashi, K., Nakajima, E., and Suzuki, K. (2006). Involvement of protein phosphatase 2A in the maintenance of E-cadherin-mediated cell-cell adhesion through recruitment of IQGAP1. J Cell Physiol 206,814-820.
Tan, B., Long, X., Nakshatri, H., Nephew, K.P., and Bigsby, R.M. (2008). Striatin-3 gamma inhibits estrogen receptor activity by recruiting a protein phosphatase. J Mol Endocrinol 40,199-210.
Tseng LM, L.C., Chang KC, Chu PY, Shiau CW, Chen KF. (2012). CIP2A is a target of bortezomib in human triple negative breast cancer cells. Breast Cancer Res 14, R68.
Vinayak, S., and Carlson, R.W. (2013). mTOR inhibitors in the treatment of breast cancer. Oncology (Williston Park) 27,38-44,46,48 passim.
Woo, M.M., Salamanca, C.M., Symowicz, J., Stack, M.S., Miller, D.M., Leung, P.C., Gilks, C.B., and Auersperg, N. (2008). SV40 early genes induce neoplastic properties in serous borderline ovarian tumor cells. Gynecol Oncol.
Xu, J., Chen, Y, and Olopade, O.I. (2010). MYC and Breast Cancer. Genes Cancer 1, 629-640.
Yang, W.H., Lan, H.Y., Huang, C.H., Tai, S.K., Tzeng, C.H., Kao, S.Y., Wu, K.J., Hung, M.C., and Yang, M.H. (2012). RAC1 activation mediates Twist1-induced cancer cell migration. Nat Cell Biol 14,366-374.
Yu, H.C., Chen, H.J., Chang, Y.L., Liu, C.Y., Shiau, C.W., Cheng, A.L., and Chen, K.F. (2013). Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma. Biochem Pharmacol 85,356-366.
Zeisberg, M., and Neilson, E.G (2009). Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119,1429-1437.
Zhou, J., Pham, H.T., Ruediger, R., and Walter, G. (2003). Characterization of the Aalpha and Abeta subunit isoforms of protein phosphatase 2A:differences in expression, subunit interaction, and evolution. Biochem J 369,387-398.
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