肝癌发展过程中促血管生成因子NogoB的转录调节机制
摘要
肝癌是我国常见恶性肿瘤之一,我国每年约有11万人死于肝癌。本室于1998年克隆的基因NogoB,又称RTN4B,属于定位于内质网膜的reticulon (RTN)蛋白家族。研究发现NogoB在神经和肌肉系统中发挥一定的作用。还有文献报道称NogoB能够诱导血管内皮细胞的迁移和粘附,并参与血管损伤后的重塑。而我们发现NogoB在正常肝组织中不表达但在肝癌组织中异常高表达。因此,我们推测并在以前的研究中证实了肝癌中高水平表达的NogoB能够促进肝癌组织内的血管生成,从而促进肝癌的发生发展。为了探讨NogoB在正常肝脏中不表达而在肝癌组织中高水平表达的原因,我们对它的转录调节机制进行了一系列研究。
随着肿瘤的快速发展,距离血管超过180μm的肿瘤细胞会发生坏死。这与氧气可扩散的距离相当。为了适应缺氧的环境,肿瘤细胞通过调节信号通路,诱导出新生血管,从而为快速持续增殖的肿瘤细胞提供充足的氧气和代谢物。缺氧诱导因子(HIF-1a)即是一个调控缺氧诱导的血管生成的关键转录因子。HIF-1α广泛存在于人和哺乳动物体内,它调控的众多靶基因都能通过促进内皮细胞的增殖和迁移而参与调节血管生成,从而使肿瘤细胞适应缺氧微环境。基于这些研究结果,我们推测新的促血管生成因子NogoB在肝癌中的高水平表达很可能也是受HIF-1α调节的。通过比较癌和癌旁组织样本中NogoB和HIF-1α的表达量,我们发现NogoB和HIF-1α都是在肝癌组织中上调表达。我们利用大鼠肝动脉结扎模型,结扎后的肝脏处于低氧环境并且诱导了NogoB的表达。用缺氧模拟化合物CoCl2处理大鼠原代肝细胞后,NogoB也能够上调表达。而后,我们用缺氧模拟化合物DFO处理肝癌细胞系,发现其中的NogoB表达量也逐渐增加,而缺氧(1%02)也可以使NogoB的表达量在肝癌细胞系中逐渐增加。为了研究NogoB受缺氧诱导是否由HIF-1a调节,我们利用荧光素酶报告系统发现HIF-1a能增强NogoB启动子的转录活性并存在剂量依赖。用慢病毒干扰内源HIF-1α后,缺氧条件下NogoB启动子的激活显著下降,这说明缺氧可以通过HIF-1a上调NogoB的转录。为了确定HIF-1是否能直接调节NogoB以及NogoB启动子上有效的HRE的位置,我们对NogoB启动子进行了生物信息学分析,发现存在两个可能的H1F-1α应答元件(HRE)。进而我们对NogoB启动子做了分段缺失,发现转录起始位点上游-4041—-991碱基之间存在HIF-1a应答元件。然后我们对转录起始位点上游-3829—-3822碱基的HRE进行点突变,在1%02或DFO处理的条件下NogoB启动子的转录活性均没有提高,说明缺氧条件下,HIF-1通过该HRE激活NogoB的启动子。然后,我们用染色质免疫沉淀法证实HIF-1α在1%02和化学模拟缺氧条件下均能在体内与NogoB启动子DNA序列上的该HRE直接结合。并且凝胶阻滞实验进一步证实HIF-1和HRE的结合是直接的,并且鉴定了具体的结合位点序列。我们的研究发现促血管生成因子NogoB受缺氧条件诱导上调表达,并通过体内体外实验探讨了HIF-1α调节NogoB表达的机制。
虽然缺氧是NogoB在肿瘤中诱导表达的重要机制,然而,许多肿瘤促血管生成因子如VEGF,在受缺氧诱导的同时也能通过其他转录因子应答肿瘤细胞的内外刺激。AP-1是一种bZIP蛋白形成的二聚体转录因子,包括Jun、Fos、ATF、MAF等蛋白家族。它可由两个Jun蛋白形成同源二聚体或由一个Jun和一个Fos蛋白形成异源二聚体,通过结合启动子上的TPA应答元件(TRE)调节靶基因的转录,从而参与肿瘤的转化、增殖、浸润、转移和血管生成等过程。我们发现与癌旁组织相比,AP-1也和NogoB一样在癌组织中上调表达。瞬时表达外源AP-1和用TPA激活内源AP-1能够提高NogoB的表达水平和启动子的转录活性。并且对NogoB转录激活是通过Jun而不是Fos实现的。A-Fos是AP-1的一个显性负突变体,而它可以抑制AP-1或TPA激活的NogoB转录活性。另外A-Fos只能抑制AP-1诱导的转录活性,而对基础转录活性的抑制作用有限,说明AP-1并不负责NogoB的基础表达。通过对NogoB启动子进行分析,我们发现存在三个可能的AP-1结合位点(TRE)。我们对NogoB启动子做了分段缺失,发现转录起始位点上游-991—-770之间的区域对于AP-1诱导NogoB转录十分重要。对启动子上这三个TRE做点突变,发现转录起始位点上游-782—-776碱基之间是AP-1应答元件。染色质免疫沉淀法证实AP-1能在体内与NogoB启动子序列上的这段DNA结合。
综上所述,本文研究发现肝癌中HIF-1 a和AP-1能够转录激活促血管生成因子NogoB的表达,即肝肿瘤快速增殖产生的缺氧微环境激活了NogoB的表达,同时肝癌中高水平的AP-1也参与了NogoB的转录激活。从而为阐明NogoB在肝癌中异常高水平表达的分子机制提供了理论依据。
Hepatocarcinoma (HCC) is one of the common malignant tumors in China.110 thousands of people died of HCC every year. NogoB, also known as RTN4B, was cloned by our lab in 1998. It is a member of reticulon (RTN) protein family which is localized in the endoplasmic reticulum. It is found that NogoB plays dual roles in both nerve and muscle system. It is also reported that NogoB takes part in vascular remodeling by promoting migration and adhesion of vascular endothelial cells. However, our group found that NogoB is expressed highly and seretedly in liver cancer compared to its expression in adjacent tumor tissue. So we presumed and confirmed in the former studies that highly expressed NogoB plays positive roles in tumor angiogenesis, and then promotes tumorigenesis in HCC. To explore the reason of the specific characterization of NogoB in HCC, we worked on its mechanism of transcriptional regulation.
Along with the uncontrolled proliferation, tumor cells that were located more than 180μm away from blood vessels were observed to necrose. This is similar to the distance that oxygen diffuses as it passes from the capillary to cells. In response to the hypoxia condition, cancer cells undergo genetic changes to induce new blood vessel to provide rapidly proliferating tumor cells with an adequate supply of oxygen and metabolites. Hypoxia inducible factor (HIF)-la is one of the key regulator in hypoxia induced angiogenesis. HIF-1a is a transcription factor widely expressed in human and mammalian. Its multiple target genes have been proved to modulate angiogenesis by promoting proliferation and migration in endothelial cells. Based on the evidence, we speculated that the overexpression of novel pro-angiogenesis factor NogoB is also regulated by HIF-la in HCC.
By comparing the expression patterns of NogoB in HCC and its normal counterpart by Western blot analyses, we found that both NogoB and HIF-la was significantly up-regulated in HCC samples in comparison to the adjacent non-tumorous liver tissues. Then we use rat hepatic artery ligation (HAL) model to make the ligated liver physiological hypoxia, and this induced the expression of NogoB. Deferoxamine (DFO) and CoCl2 could mimic hypoxia conditions by means of stabilizing HIF-1α. In CoCl2 treated rat primary liver cells, increased expression of NogoB was also observed. By using hepatocarcinoma cell lines as a model, we found that in response to DFO or hypoxic condition, the expression of NogoB increased in a time-dependent manner. To determine whether elevated expression of NogoB was mediated by HIF-la, we utilized luciferase assay. The result showed that transfected HIF-la . increased the NogoB promoter activity in a dose-dependent manner and lentivirus delivery of HIF-1a siRNA reduced the NogoB promoter activity in hypoxia condition. Analysis of the NogoB promoter showed two predicted hypoxia response elements (HRE). To identify the HIF-la binding site in NogoB promoter, a series of NogoB promoter deletion constructs was generated. The promoter region responsible to hypoxia span from-4041 to-991 relative to transcription start site. Then a site-directed mutant was constructed at putative HRE located-3829 to-3822 upstream of transcription start site. No significant increase of NogoB promoter activity was detected either in hypoxia or in DFO treated culture. Chromatin immunoprecipitation assay (ChIP) proved that HIF-la protein is bound to the distal HRE. A gel mobility shift assay confirmed that the interaction between HIF-1 and the HRE in the NogoB promoter is direct. Our observation suggeted that hypoxia may play a central role in NogoB upregulation in HCC and further elucidate the molecular mechanisms responsible for hypoxia mediated induction of NogoB expression in HCC cells.
That hypoxia strongly induced NogoB is an important mechanism of induction in tumor. However, many tumor-associatied angiogenetic factors could also be elevated by other transcriptional factors in response to diverse simuli. The AP-1 (activator protein 1) transcription factor, known as basic leucine-zipper (bZIP) protein, is a dimeric complex which is composed of Jun, Fos, ATF and Maf protein families. The Jun proteins could form homodimers or heterodimers with Fos proteins which dimerize with Jun proteins to enhance their DNA-binding activity. By binding to the TPA response element (TRE) in the promoter, AP-1 complex transcriptional regulates the expression of target genes and thereby plays a role in the proliferation, invasion, metastasis, transformation and angiogenesis of tumors. Our data indicated both NogoB and AP-1 was significantly up-regulated in HCC samples in comparison to the adjacent non-tumorous liver tissues. Transient expression of AP-1 and activation of endogenous AP-1 by treatment with TPA increased the NogoB expression and its promoter activity. And the induction of NogoB promoter activity was mediated by c-Fos but not c-Jun. A-Fos, a dominant negative construct of AP-1, showed to inhibit AP-1-dependent and TPA induced NogoB promoter activity. The A-Fos was able to prevent AP-1 induction of the promoter activity, but only slightly decreased the basal activity of the promoter. This indicated that constitutive NogoB expression is only slightly due to the effect of AP-1. Bioinformatic analysis revealed three putative AP-1 response elements. Sequential deletion of the promoter revealed that the region located upstream of transcription initiation site (-991/-770) was essential for AP-1 induction of NogoB transcription. Site-directed mutation analysis of three potential AP-1 binding sites suggested that the distal element at-782bp to-776bp was responsible for the induction, which was confirmed by chromatin immunoprecipitation.
In conclusion, our results provided the molecular basis that the overexpression of NogoB was mainly induced by HIF-la in hypoxic condition. Meanwhile AP-1 also played an important role in regulation of NogoB in response to diverse simuli.
随着肿瘤的快速发展,距离血管超过180μm的肿瘤细胞会发生坏死。这与氧气可扩散的距离相当。为了适应缺氧的环境,肿瘤细胞通过调节信号通路,诱导出新生血管,从而为快速持续增殖的肿瘤细胞提供充足的氧气和代谢物。缺氧诱导因子(HIF-1a)即是一个调控缺氧诱导的血管生成的关键转录因子。HIF-1α广泛存在于人和哺乳动物体内,它调控的众多靶基因都能通过促进内皮细胞的增殖和迁移而参与调节血管生成,从而使肿瘤细胞适应缺氧微环境。基于这些研究结果,我们推测新的促血管生成因子NogoB在肝癌中的高水平表达很可能也是受HIF-1α调节的。通过比较癌和癌旁组织样本中NogoB和HIF-1α的表达量,我们发现NogoB和HIF-1α都是在肝癌组织中上调表达。我们利用大鼠肝动脉结扎模型,结扎后的肝脏处于低氧环境并且诱导了NogoB的表达。用缺氧模拟化合物CoCl2处理大鼠原代肝细胞后,NogoB也能够上调表达。而后,我们用缺氧模拟化合物DFO处理肝癌细胞系,发现其中的NogoB表达量也逐渐增加,而缺氧(1%02)也可以使NogoB的表达量在肝癌细胞系中逐渐增加。为了研究NogoB受缺氧诱导是否由HIF-1a调节,我们利用荧光素酶报告系统发现HIF-1a能增强NogoB启动子的转录活性并存在剂量依赖。用慢病毒干扰内源HIF-1α后,缺氧条件下NogoB启动子的激活显著下降,这说明缺氧可以通过HIF-1a上调NogoB的转录。为了确定HIF-1是否能直接调节NogoB以及NogoB启动子上有效的HRE的位置,我们对NogoB启动子进行了生物信息学分析,发现存在两个可能的H1F-1α应答元件(HRE)。进而我们对NogoB启动子做了分段缺失,发现转录起始位点上游-4041—-991碱基之间存在HIF-1a应答元件。然后我们对转录起始位点上游-3829—-3822碱基的HRE进行点突变,在1%02或DFO处理的条件下NogoB启动子的转录活性均没有提高,说明缺氧条件下,HIF-1通过该HRE激活NogoB的启动子。然后,我们用染色质免疫沉淀法证实HIF-1α在1%02和化学模拟缺氧条件下均能在体内与NogoB启动子DNA序列上的该HRE直接结合。并且凝胶阻滞实验进一步证实HIF-1和HRE的结合是直接的,并且鉴定了具体的结合位点序列。我们的研究发现促血管生成因子NogoB受缺氧条件诱导上调表达,并通过体内体外实验探讨了HIF-1α调节NogoB表达的机制。
虽然缺氧是NogoB在肿瘤中诱导表达的重要机制,然而,许多肿瘤促血管生成因子如VEGF,在受缺氧诱导的同时也能通过其他转录因子应答肿瘤细胞的内外刺激。AP-1是一种bZIP蛋白形成的二聚体转录因子,包括Jun、Fos、ATF、MAF等蛋白家族。它可由两个Jun蛋白形成同源二聚体或由一个Jun和一个Fos蛋白形成异源二聚体,通过结合启动子上的TPA应答元件(TRE)调节靶基因的转录,从而参与肿瘤的转化、增殖、浸润、转移和血管生成等过程。我们发现与癌旁组织相比,AP-1也和NogoB一样在癌组织中上调表达。瞬时表达外源AP-1和用TPA激活内源AP-1能够提高NogoB的表达水平和启动子的转录活性。并且对NogoB转录激活是通过Jun而不是Fos实现的。A-Fos是AP-1的一个显性负突变体,而它可以抑制AP-1或TPA激活的NogoB转录活性。另外A-Fos只能抑制AP-1诱导的转录活性,而对基础转录活性的抑制作用有限,说明AP-1并不负责NogoB的基础表达。通过对NogoB启动子进行分析,我们发现存在三个可能的AP-1结合位点(TRE)。我们对NogoB启动子做了分段缺失,发现转录起始位点上游-991—-770之间的区域对于AP-1诱导NogoB转录十分重要。对启动子上这三个TRE做点突变,发现转录起始位点上游-782—-776碱基之间是AP-1应答元件。染色质免疫沉淀法证实AP-1能在体内与NogoB启动子序列上的这段DNA结合。
综上所述,本文研究发现肝癌中HIF-1 a和AP-1能够转录激活促血管生成因子NogoB的表达,即肝肿瘤快速增殖产生的缺氧微环境激活了NogoB的表达,同时肝癌中高水平的AP-1也参与了NogoB的转录激活。从而为阐明NogoB在肝癌中异常高水平表达的分子机制提供了理论依据。
Hepatocarcinoma (HCC) is one of the common malignant tumors in China.110 thousands of people died of HCC every year. NogoB, also known as RTN4B, was cloned by our lab in 1998. It is a member of reticulon (RTN) protein family which is localized in the endoplasmic reticulum. It is found that NogoB plays dual roles in both nerve and muscle system. It is also reported that NogoB takes part in vascular remodeling by promoting migration and adhesion of vascular endothelial cells. However, our group found that NogoB is expressed highly and seretedly in liver cancer compared to its expression in adjacent tumor tissue. So we presumed and confirmed in the former studies that highly expressed NogoB plays positive roles in tumor angiogenesis, and then promotes tumorigenesis in HCC. To explore the reason of the specific characterization of NogoB in HCC, we worked on its mechanism of transcriptional regulation.
Along with the uncontrolled proliferation, tumor cells that were located more than 180μm away from blood vessels were observed to necrose. This is similar to the distance that oxygen diffuses as it passes from the capillary to cells. In response to the hypoxia condition, cancer cells undergo genetic changes to induce new blood vessel to provide rapidly proliferating tumor cells with an adequate supply of oxygen and metabolites. Hypoxia inducible factor (HIF)-la is one of the key regulator in hypoxia induced angiogenesis. HIF-1a is a transcription factor widely expressed in human and mammalian. Its multiple target genes have been proved to modulate angiogenesis by promoting proliferation and migration in endothelial cells. Based on the evidence, we speculated that the overexpression of novel pro-angiogenesis factor NogoB is also regulated by HIF-la in HCC.
By comparing the expression patterns of NogoB in HCC and its normal counterpart by Western blot analyses, we found that both NogoB and HIF-la was significantly up-regulated in HCC samples in comparison to the adjacent non-tumorous liver tissues. Then we use rat hepatic artery ligation (HAL) model to make the ligated liver physiological hypoxia, and this induced the expression of NogoB. Deferoxamine (DFO) and CoCl2 could mimic hypoxia conditions by means of stabilizing HIF-1α. In CoCl2 treated rat primary liver cells, increased expression of NogoB was also observed. By using hepatocarcinoma cell lines as a model, we found that in response to DFO or hypoxic condition, the expression of NogoB increased in a time-dependent manner. To determine whether elevated expression of NogoB was mediated by HIF-la, we utilized luciferase assay. The result showed that transfected HIF-la . increased the NogoB promoter activity in a dose-dependent manner and lentivirus delivery of HIF-1a siRNA reduced the NogoB promoter activity in hypoxia condition. Analysis of the NogoB promoter showed two predicted hypoxia response elements (HRE). To identify the HIF-la binding site in NogoB promoter, a series of NogoB promoter deletion constructs was generated. The promoter region responsible to hypoxia span from-4041 to-991 relative to transcription start site. Then a site-directed mutant was constructed at putative HRE located-3829 to-3822 upstream of transcription start site. No significant increase of NogoB promoter activity was detected either in hypoxia or in DFO treated culture. Chromatin immunoprecipitation assay (ChIP) proved that HIF-la protein is bound to the distal HRE. A gel mobility shift assay confirmed that the interaction between HIF-1 and the HRE in the NogoB promoter is direct. Our observation suggeted that hypoxia may play a central role in NogoB upregulation in HCC and further elucidate the molecular mechanisms responsible for hypoxia mediated induction of NogoB expression in HCC cells.
That hypoxia strongly induced NogoB is an important mechanism of induction in tumor. However, many tumor-associatied angiogenetic factors could also be elevated by other transcriptional factors in response to diverse simuli. The AP-1 (activator protein 1) transcription factor, known as basic leucine-zipper (bZIP) protein, is a dimeric complex which is composed of Jun, Fos, ATF and Maf protein families. The Jun proteins could form homodimers or heterodimers with Fos proteins which dimerize with Jun proteins to enhance their DNA-binding activity. By binding to the TPA response element (TRE) in the promoter, AP-1 complex transcriptional regulates the expression of target genes and thereby plays a role in the proliferation, invasion, metastasis, transformation and angiogenesis of tumors. Our data indicated both NogoB and AP-1 was significantly up-regulated in HCC samples in comparison to the adjacent non-tumorous liver tissues. Transient expression of AP-1 and activation of endogenous AP-1 by treatment with TPA increased the NogoB expression and its promoter activity. And the induction of NogoB promoter activity was mediated by c-Fos but not c-Jun. A-Fos, a dominant negative construct of AP-1, showed to inhibit AP-1-dependent and TPA induced NogoB promoter activity. The A-Fos was able to prevent AP-1 induction of the promoter activity, but only slightly decreased the basal activity of the promoter. This indicated that constitutive NogoB expression is only slightly due to the effect of AP-1. Bioinformatic analysis revealed three putative AP-1 response elements. Sequential deletion of the promoter revealed that the region located upstream of transcription initiation site (-991/-770) was essential for AP-1 induction of NogoB transcription. Site-directed mutation analysis of three potential AP-1 binding sites suggested that the distal element at-782bp to-776bp was responsible for the induction, which was confirmed by chromatin immunoprecipitation.
In conclusion, our results provided the molecular basis that the overexpression of NogoB was mainly induced by HIF-la in hypoxic condition. Meanwhile AP-1 also played an important role in regulation of NogoB in response to diverse simuli.
引文
1. Folkman J:Tumor angiogenesis:therapeutic implications. N Engl J Med 1971, 285(21):1182-1186.
2. Brem S, Brem H, Folkman J, Finkelstein D, Patz A:Prolonged tumor dormancy by prevention of neovascularization in the vitreous. Cancer Res 1976,36(8):2807-2812.
3. Parangi S, O'Reilly M, Christofori G, Holmgren L, Grosfeld J, Folkman J, Hanahan D:Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proc Natl Acad Sci U S A 1996,93(5):2002-2007.
4. Holmgren L, O'Reilly MS, Folkman J:Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995,1(2):149-153.
5. Hanahan D, Weinberg RA:The hallmarks of cancer. Cell 2000,100(1):57-70.
6. Ferrara N, Hillan KJ, Gerber HP, Novotny W:Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004,3(5):391-400.
7. Ribatti D, Vacca A, Presta M:The discovery of angiogenic factors:a historical review. Gen Pharmacol 2000,35(5):227-231.
8. Carmeliet P, Jain RK:Angiogenesis in cancer and other diseases. Nature 2000, 407(6801):249-257.
9. Miller KD:Issues and challenges for antiangiogenic therapies. Breast Cancer Res Treat 2002,75 Suppl 1:S45-50; discussion S57-48.
10. BI Anding YL, YANG Jun, ZHANG Min, ZHOU Yi & ZHAO Shouyuan: Cloning and expression analysis of human reticulon 4c cDNA. Chinese Science Bulletin 2000,45:1862-1868.
11. Acevedo L, Yu J, Erdjument-Bromage H, Miao RQ, Kim JE, Fulton D, Tempst P, Strittmatter SM, Sessa WC:A new role for Nogo as a regulator of vascular remodeling. Nat Med 2004,10(4):382-388.
12. Pugh CW, Ratcliffe PJ:Regulation of angiogenesis by hypoxia:role of the HIF system. Nat Med 2003,9(6):677-684.
13. Guillemin K, Krasnow MA:The hypoxic response:huffing and HIFing. Cell 1997,89(1):9-12.
14. Beck I, Weinmann R, Caro J:Characterization of hypoxia-responsive enhancer in the human erythropoietin gene shows presence of hypoxia-inducible 120-Kd nuclear DNA-binding protein in erythropoietin-producing and nonproducing cells. Blood 1993,82(3):704-711.
15. Shaulian E, Karin M:AP-1 in cell proliferation and survival. Oncogens 2001, 20(19):2390-2400.
16. Halazonetis TD, Georgopoulos K, Greenberg ME, Leder P:c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities. Cell 1988,55(5):917-924.
17. Ryseck RP, Bravo R:c-JUN, JUN B, and JUN D differ in their binding affinities to AP-1 and CRE consensus sequences:effect of FOS proteins. Oncogene 1991,6(4):533-542.
18. van Dam H, Castellazzi M:Distinct roles of Jun:Fos and Jun:ATF dimers in oncogenesis. Oncogene 2001,20(19):2453-2464.
19. Shaulian E, Karin M:AP-1 as a regulator of cell life and death. Nat Cell Biol 2002,4(5):E131-136.
20. Jochum W, Passegue E, Wagner EF:AP-1 in mouse development and tumorigenesis. Oncogene 2001,20(19):2401-2412.
21. Hu E, Mueller E, Oliviero S, Papaioannou VE, Johnson R, Spiegelman BM: Targeted disruption of the c-fos gene demonstrates c-fos-dependent and-independent pathways for gene expression stimulated by growth factors or oncogenes. Embo J 1994,13(13):3094-3103.
22. Kustikova O, Kramerov D, Grigorian M, Berezin V, Bock E, Lukanidin E, Tulchinsky E:Fra-1 induces morphological transformation and increases in vitro invasiveness and motility of epithelioid adenocarcinoma cells. Mol Cell Biol 1998,18(12):7095-7105.
23. Marconcini L, Marchio S, Morbidelli L, Cartocci E, Albini A, Ziche M, Bussolino F, Oliviero S:c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro. Proc Natl Acad Sci USA 1999,96(17):9671-9676.
24. Toft DJ, Rosenberg SB, Bergers G, Volpert O, Linzer DI:Reactivation of proliferin gene expression is associated with increased angiogenesis in a cell culture model of fibrosarcoma tumor progression. Proc Natl Acad Sci U S A 2001,98(23):13055-13059.
25. Greenberg ME, Ziff EB:Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature 1984,311(5985):433-438.
26. Wang GL, Semenza GL:Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 1993, 268(29):21513-21518.
27. Pore N, Liu S, Shu HK, Li B, Haas-Kogan D, Stokoe D, Milanini-Mongiat J, Pages G, O'Rourke DM, Bernhard E et al:Spl is involved in Akt-mediated induction of VEGF expression through an HIF-1-independent mechanism. Mol Biol Cell 2004,15(11):4841-4853.
28. Yuen MF, Wu PC, Lai VC, Lau JY, Lai CL:Expression of c-Myc, c-Fos, and c-jun in hepatocellular carcinoma. Cancer 2001,91 (1):106-112.
29. Borlak J, Meier T, Halter R, Spanel R, Spanel-Borowski K:Epidermal growth factor-induced hepatocellular carcinoma:gene expression profiles in precursor lesions, early stage and solitary tumours. Oncogene 2005,24(11):1809-1819.
1. Rosenquist M, Alsterfjord M, Larsson C, Sommarin M:Data mining the Arabidopsis genome reveals fifteen 14-3-3 genes. Expression is demonstrated for two out of five novel genes. Plant Physiol 2001,127(1):142-149.
2. Wang W, Shakes DC:Molecular evolution of the 14-3-3 protein family. J Mol Evol 1996,43(4):384-398.
3. Moore BW, Perez VJ:Specific acidic proteins of the nervous system. In: Physiological and Biochemical Aspects of Nervous Integration. Edited by Carlson FD. Prentice-Hall, Englewood Cliffs, NJ; 1968:343-359.
4. Ichimura T, Isobe T, Okuyama T, Yamauchi T, Fujisawa H:Brain 14-3-3 protein is an activator protein that activates tryptophan 5-monooxygenase and tyrosine 3-monooxygenase in the presence of Ca2+,calmodulin-dependent protein kinase II. FEBS Lett 1987,219(l):79-82.
5. Toker A, Ellis CA, Sellers LA, Aitken A:Protein kinase C inhibitor proteins. Purification from sheep brain and sequence similarity to lipocortins and 14-3-3 protein. Eur J Biochem 1990,191(2):421-429.
6. Fantl WJ, Muslin AJ, Kikuchi A, Martin JA, MacNicol AM, Gross RW, Williams LT:Activation of Raf-1 by 14-3-3 proteins. Nature 1994, 371(6498):612-614.
7. Fu H, Xia K, Pallas DC, Cui C, Conroy K, Narsimhan RP, Mamon H, Collier RJ, Roberts TM:Interaction of the protein kinase Raf-1 with 14-3-3 proteins. Science 1994,266(5182):126-129.
8. Freed E, Symons M, Macdonald SQ McCormick F, Ruggieri R:Binding of 14-3-3 proteins to the protein kinase Raf and effects on its activation. Science 1994,265(5179):1713-1716.
9. Thorson JA, Yu LW, Hsu AL, Shih NY, Graves PR, Tanner JW, Allen PM, Piwnica-Worms H, Shaw AS:14-3-3 proteins are required for maintenance of Raf-1 phosphorylation and kinase activity. Mol Cell Biol 1998, 18(9):5229-5238.
10. Muslin AJ, Tanner JW, Allen PM, Shaw AS:Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell 1996, 84(6):889-897.
11. Xiao B, Smerdon SJ, Jones DH, Dodson GG, Soneji Y, Aitken A, Gamblin SJ: Structure of a 14-3-3 protein and implications for coordination of multiple signalling pathways. Nature 1995,376(6536):188-191.
12. Liu D, Bienkowska J, Petosa C, Collier RJ, Fu H, Liddington R:Crystal structure of the zeta isoform of the 14-3-3 protein. Nature 1995, 376(6536):191-194.
13. Luo ZJ, Zhang XF, Rapp U, Avruch J:Identification of the 14.3.3 zeta domains important for self-association and Raf binding. J Biol Chem 1995, 270(40):23681-23687.
14. Tzivion G, Luo Z, Avruch J:A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity. Nature 1998,394(6688):88-92.
15. Zhang L, Wang H, Liu D, Liddington R, Fu H:Raf-1 kinase and exoenzyme S interact with 14-3-3zeta through a common site involving lysine 49. J Biol Chem 1997,272(21):13717-13724.
16. Wang H, Zhang L, Liddington R, Fu H:Mutations in the hydrophobic surface of an amphipathic groove of 14-3-3zeta disrupt its interaction with Raf-1 kinase. J Biol Chem 1998,273(26):16297-16304.
17. Rittinger K, Budman J, Xu J, Volinia S, Cantley LC, Smerdon SJ, Gamblin SJ, Yaffe MB:Structural analysis of 14-3-3 phosphopeptide complexes identifies a dual role for the nuclear export signal of 14-3-3 in ligand binding. Mol Cell 1999,4(2):153-166.
18. Roseboom PH, Weller JL, Babila T, Aitken A, Sellers LA, Moffett JR, Namboodiri MA, Klein DC:Cloning and characterization of the epsilon and zeta isoforms of the 14-3-3 proteins. DNA Cell Biol 1994,13(6):629-640.
19. Cardoso C, Leventer RJ, Ward HL, Toyo-Oka K, Chung J, Gross A, Martin CL, Allanson J, Pilz DT, Olney AH et at Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 2003,72(4):918-930.
20. Wiltfang J, Otto M, Baxter HC, Bodemer M, Steinacker P, Bahn E, Zerr I, Kornhuber J, Kretzschmar HA, Poser S el al: Isoform pattern of 14-3-3 proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. J Neurochem 1999,73(6):2485-2490.
21. Fountoulakis M, Cairns N, Lubec G:Increased levels of 14-3-3 gamma and epsilon proteins in brain of patients with Alzheimer's disease and Down syndrome. J Neural Transm Suppl 1999,57:323-335.
22. Oriente F, Andreozzi F, Romano C, Perruolo G, Perfetti A, Fiory F, Miele C, Beguinot F, Formisano P:Protein kinase C-alpha regulates insulin action and degradation by interacting with insulin receptor substrate-1 and 14-3-3 epsilon. JBiol Chem 2005,280(49):40642-40649.
23. Chang HC, Rubin GM:14-3-3 epsilon positively regulates Ras-mediated signaling in Drosophila. Genes Dev 1997,11 (9):1132-1139.
24. Gu M, Du X:A novel ligand-binding site in the zeta-form 14-3-3 protein recognizing the platelet glycoprotein Ibalpha and distinct from the c-Raf-binding site. J Biol Chem 1998,273(50):33465-33471.
25. Zhou Y, Reddy S, Murrey H, Fei H, Levitan IB:Monomeric 14-3-3 protein is sufficient to modulate the activity of the Drosophila slowpoke calcium-dependent potassium channel. J Biol Chem 2003, 278(12):10073-10080.
26. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG:The CLUSTAL_X windows interface:flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 1997, 25(24):4876-4882.
27. Yang X, Lee WH, Sobott F, Papagrigoriou E, Robinson CV, Grossmann JG, Sundstrom M, Doyle DA, Elkins JM:Structural basis for protein-protein interactions in the 14-3-3 protein family. Proc Natl Acad Sci USA 2006, 103(46):17237-17242.
1. Folkman J:Tumor angiogenesis:therapeutic implications. N Engl J Med 1971, 285(21):1182-1186.
2. Gimbrone MA, Jr., Leapman SB, Cotran RS, Folkman J:Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 1972,136(2):261-276.
3. Brem S, Brem H, Folkman J, Finkelstein D, Patz A:Prolonged tumor dormancy by prevention of neovascularization in the vitreous. Cancer Res 1976,36(8):2807-2812.
4. Parangi S, O'Reilly M, Christofori G, Holmgren L, Grosfeld J, Folkman J, Hanahan D:Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proc Natl Acad Sci USA 1996,93(5):2002-2007.
5. Holmgren L, O'Reilly MS, Folkman J:Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995,1(2):149-153.
6. Carmeliet P:Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000, 6(4):389-395.
7. Bergers G, Benjamin LE:Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003,3(6):401-410.
8. Naumov GN, Akslen LA, Folkman J:Role of angiogenesis in human tumor dormancy:animal models of the angiogenic switch. Cell Cycle 2006, 5(16):1779-1787.
9. Folkman J, Watson K, Ingber D, Hanahan D:Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989,339(6219):58-61.
10. North S, Moenner M, Bikfalvi A:Recent developments in the regulation of the angiogenic switch by cellular stress factors in tumors. Cancer Lett 2005, 218(1):1-14.
11. Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, Pollard JW:Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 2006,66(23):11238-11246.
12. Nozawa H, Chiu C, Hanahan D:Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A 2006,103(33):12493-12498.
13. Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ:Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999, 284(5422):1994-1998.
14. Giordano FJ, Johnson RS:Angiogenesis:the role of the microenvironment in flipping the switch. Curr Opin Genet Dev2001, 11(1):35-40.
15. Hockel M, Vaupel P:Tumor hypoxia:definitions and current clinical, biologic, and molecular aspects. JNatl Cancer Inst 2001,93(4):266-276.
16. Hockel M, Schlenger K, Hockel S, Vaupel P:Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res 1999, 59(18):4525-4528.
17. Semenza GL:Hydroxylation of HIF-1:oxygen sensing at the molecular level. Physiology (Bethesda) 2004,19:176-182.
18. Peng J, Zhang L, Drysdale L, Fong GH:The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Proc Natl Acad Sci U S A 2000,97(15):8386-8391.
19. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y:A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor lalpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A 1997, 94(9):4273-4278.
20. Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L:Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 2001, 414(6863):550-554.
21. Carrero P, Okamoto K, Coumailleau P, O'Brien S, Tanaka H, Poellinger L: Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor lalpha. Mol Cell Biol 2000, 20(1):402-415.
22. Lando D, Pongratz I, Poellinger L, Whitelaw ML:A redox mechanism controls differential DNA binding activities of hypoxia-inducible factor (HIF) 1 alpha and the HIF-like factor. J Biol Chem 2000,275(7):4618-4627.
23. Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH:Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. JBiol Chem 2000,275(33):25733-25741.
24. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG:Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000,2(7):423-427.
25. Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW: Activation of HIFl alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci U S A 2000, 97(19):10430-10435.
26. Tanimoto K, Makino Y, Pereira T, Poellinger L:Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. Embo J 2000,19(16):4298-4309.
27. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ:The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999,399(6733):271-275.
28. Stebbins CE, Kaelin WG, Jr., Pavletich NP:Structure of the VHL-ElonginC-ElonginB complex:implications for VHL tumor suppressor function. Science 1999,284(5413):455-461.
29. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ et al: Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001,292(5516):468-472.
30. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG, Jr.:HIFalpha targeted for VHL-mediated destruction by proline hydroxylation:implications for 02 sensing. Science 2001, 292(5516):464-468.
31. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ:Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. Embo J 2001,20(18):5197-5206.
32. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT:Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-lalpha during hypoxia:a mechanism of 02 sensing. J Biol Chem 2000, 275(33):25130-25138.
33. Srinivas V, Leshchinsky I, Sang N, King MP, Minchenko A, Caro J:Oxygen sensing and HIF-1 activation does not require an active mitochondrial respiratory chain electron-transfer pathway. J Biol Chem 2001, 276(25):21995-21998.
34. Vaux EC, Metzen E, Yeates KM, Ratcliffe PJ:Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain. Blood 2001,98(2):296-302.
35. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A et al:C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001,107(1):43-54.
36. Bruick RK, McKnight SL:A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001,294(5545):1337-1340.
37. Mahon PC, Hirota K, Semenza GL:FIH-1:a novel protein that interacts with HIF-lalpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 2001,15(20):2675-2686.
38. Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK:FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 2002,16(12):1466-1471.
39. Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM:An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci USA 1996,93(23):12969-12973.
40. Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J:p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor lalpha (HIF-lalpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 1999,274(46):32631-32637.
41. Mylonis I, Chachami G, Samiotaki M, Panayotou G, Paraskeva E, Kalousi A, Georgatsou E, Bonanou S, Simos G:Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1 alpha. J Biol Chem 2006,281(44):33095-33106.
42. Shaw RJ, Cantley LC:Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006,441(7092):424-430.
43. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL:Modulation of hypoxia-inducible factor lalpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AK.T/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000, 60(6):1541-1545.
44. Blancher C, Moore JW, Robertson N, Harris AL:Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-lalpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway. Cancer Res 2001,61(19):7349-7355.
45. Poulaki V, Mitsiades CS, McMullan C, Sykoutri D, Fanourakis G, Kotoula V, Tseleni-Balafouta S, Koutras DA, Mitsiades N:Regulation of vascular endothelial growth factor expression by insulin-like growth factor I in thyroid carcinomas.J Clin Endocrinol Metab 2003,88(11):5392-5398.
46. Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB et al:Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 2000,14(4):391-396.
47. Grunstein J, Masbad JJ, Hickey R, Giordano F, Johnson RS:Isoforms of vascular endothelial growth factor act in a coordinate fashion To recruit and expand tumor vasculature. Mol Cell Biol 2000,20(19):7282-7291.
48. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 1996,16(9):4604-4613.
49. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L:VEGF receptor signalling-in control of vascular function. Nat Rev Mol Cell Biol 2006, 7(5):359-371.
50. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, Powell-Braxton L, Hillan KJ, Moore MW:Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996, 380(6573):439-442.
51. Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D, Johnson RS: Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res 1999, 59(7):1592-1598.
52. Jensen RL, Ragel BT, Whang K, Gillespie D:Inhibition of hypoxia inducible factor-lalpha (HIF-lalpha) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in malignant gliomas. J Neurooncol 2006, 78(3):233-247.
53. Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, van Diest PJ, van der Wall E:Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 2001,93(4):309-314.
54. Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW, Ratcliffe PJ:Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 1997,94(15):8104-8109.
55. Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP, Ferrara N, Johnson RS:Loss of HIF-1 alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 2004, 6(5):485-495.
56. Das B, Yeger H, Tsuchida R, Torkin R, Gee MF, Thorner PS, Shibuya M, Malkin D, Baruchel S:A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxia-inducible factor-1 alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. Cancer Res 2005,65(16):7267-7275.
57. Morbidelli L, Donnini S, Ziche M:Role of nitric oxide in the modulation of angiogenesis. Curr Pharm Des 2003,9(7):521-530.
58. Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura T, D'Acquisto F, Addeo R, Makuuchi M, Esumi H:Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide:control of hypoxia-inducible factor-1 activity by nitric oxide. ,95(1):189-197.
59. Palmer LA, Semenza GL, Stoler MH, Johns RA:Hypoxia induces type Ⅱ NOS gene expression in pulmonary artery endothelial cells via HIF-1. Am J Physiol 1998,274(2 Pt 1):L212-219.
60. Jung F, Palmer LA, Zhou N, Johns RA:Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes. Circ Res 2000,86(3):319-325.
61. Coulet F, Nadaud S, Agrapart M, Soubrier F:Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter. J Biol Chem 2003,278(47):46230-46240.
62. Cooke JP:NO and angiogenesis. Atheroscler Suppl 2003,4(4):53-60.
63. Rossig L, Fichtlscherer B, Breitschopf K, Haendeler J, Zeiher AM, Mulsch A, Dimmeler S:Nitric oxide inhibits caspase-3 by S-nitrosation in vivo. J Biol Chem 1999,274(11):6823-6826.
64. Ellies LG, Fishman M, Hardison J, Kleeman J, Maglione JE, Manner CK, Cardiff RD, MacLeod CL:Mammary tumor latency is increased in mice lacking the inducible nitric oxide synthase. Int J Cancer 2003,106(1):1-7.
65. Cullis ER, Kalber TL, Ashton SE, Cartwright JE, Griffiths JR, Ryan AJ, Robinson SP:Tumour overexpression of inducible nitric oxide synthase (iNOS) increases angiogenesis and may modulate the anti-tumour effects of the vascular disrupting agent ZD6126. Microvasc Res 2006,71(2):76-84.
66. Grose R, Dickson C:Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev 2005,16(2):179-186.
67. Shi YH, Wang YX, Bingle L, Gong LH, Heng WJ, Li Y, Fang WG:In vitro study of HIF-1 activation and VEGF release by bFGF in the T47D breast cancer cell line under normoxic conditions:involvement of PI-3K/Akt and MEK1/ERK pathways. J Pathol 2005,205(4):530-536.
68. Pore N, Liu S, Haas-Kogan DA, O'Rourke DM, Maity A:PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. Cancer Res 2003, 63(1):236-241.
69. Calvani M, Rapisarda A, Uranchimeg B, Shoemaker RH, Melillo G:Hypoxic induction of an HIF-1 alpha-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells. Blood 2006,107(7):2705-2712.
70. Li J, Shworak NW, Simons M:Increased responsiveness of hypoxic endothelial cells to FGF2 is mediated by HIF-1 alpha-dependent regulation of enzymes involved in synthesis of heparan sulfate FGF2-binding sites.J Cell Sci 2002,115(Pt9):1951-1959.
71. Brat DJ, Mapstone TB:Malignant glioma physiology:cellular response to hypoxia and its role in tumor progression. Ann Intern Med 2003, 138(8):659-668.
72. Arteaga CL:Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 2002,7 Suppl 4:31-39.
73. Ueda S, Basaki Y, Yoshie M, Ogawa K, Sakisaka S, Kuwano M, Ono M: PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib. Cancer Res 2006,66(10):5346-5353.
74. Lederle W, Stark HJ, Skobe M, Fusenig NE, Mueller MM:Platelet-derived growth factor-BB controls epithelial tumor phenotype by differential growth factor regulation in stromal cells. Am JPathol 2006,169(5):1767-1783.
75. Nakamura K, Taguchi E, Miura T, Yamamoto A, Takahashi K, Bichat F, Guilbaud N, Hasegawa K, Kubo K, Fujiwara Y et al: KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res 2006,66(18):9134-9142.
76. Mizukami Y, Li J, Zhang X, Zimmer MA, Iliopoulos O, Chung DC: Hypoxia-inducible factor-1-independent regulation of vascular endothelial growth factor by hypoxia in colon cancer. Cancer Res 2004,64(5):1765-1772.
77. Mizukami Y, Fujiki K, Duerr EM, Gala M, Jo WS, Zhang X, Chung DC: Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc.J Biol Chem 2006,281(20):13957-13963.
78. Jin HG, Yamashita H, Nagano Y, Fukuba H, Hiji M, Ohtsuki T, Takahashi T, Kohriyama T, Kaibuchi K, Matsumoto M:Hypoxia-induced upregulation of endothelial small G protein RhoA and Rho-kinase/ROCK2 inhibits eNOS expression. NeurosciLett 2006,408(1):62-67.
79. Chandel NS, Trzyna WC, McClintock DS, Schumacker PT:Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin. J Immunol 2000,165(2):1013-1021.
80. Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, Godson C, Nielsen JE, Moynagh P, Pouyssegur J et al: Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci U S A 2006, 103(48):18154-18159.
81. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB: NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 1999,401(6748):82-85.
82. Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ:Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res 2000,60(19):5334-5339.
83. Fujioka S, Sclabas GM, Schmidt C, Niu J, Frederick WA, Dong QG, Abbruzzese JL, Evans DB, Baker C, Chiao PJ:Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses tumorigenesis. Oncogene 2003,22(9):1365-1370.
84. Kiriakidis S, Andreakos E, Monaco C, Foxwell B, Feldmann M, Paleolog E: VEGF expression in human macrophages is NF-kappaB-dependent:studies using adenoviruses expressing the endogenous NF-kappaB inhibitor IkappaBalpha and a kinase-defective form of the IkappaB kinase 2.J Cell Sci 2003,116(Pt 4):665-674.
85. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA:The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991, 266(18):11947-11954.
86. Fujioka S, Niu J, Schmidt C, Sclabas GM, Peng B, Uwagawa T, Li Z, Evans DB, Abbruzzese JL, Chiao PJ:NF-kappaB and AP-1 connection:mechanism of NF-kappaB-dependent regulation of AP-1 activity. Mol Cell Biol 2004, 24(17):7806-7819.
87. Salnikow K, Kluz T, Costa M, Piquemal D, Demidenko ZN, Xie K, Blagosklonny MV:The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia. Mol Cell Biol 2002,22(6):1734-1741.
88. Jung YJ, Isaacs JS, Lee S, Trepel J, Neckers L:IL-1 beta-mediated up-regulation of HIF-1 alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. Faseb J 2003, 17(14):2115-2117.
89. Bonello S, Zahringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, Kietzmann T, Gorlach A:Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arterioscler Thromb Vasc Biol 2007, 27(4):755-761.
2. Brem S, Brem H, Folkman J, Finkelstein D, Patz A:Prolonged tumor dormancy by prevention of neovascularization in the vitreous. Cancer Res 1976,36(8):2807-2812.
3. Parangi S, O'Reilly M, Christofori G, Holmgren L, Grosfeld J, Folkman J, Hanahan D:Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proc Natl Acad Sci U S A 1996,93(5):2002-2007.
4. Holmgren L, O'Reilly MS, Folkman J:Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995,1(2):149-153.
5. Hanahan D, Weinberg RA:The hallmarks of cancer. Cell 2000,100(1):57-70.
6. Ferrara N, Hillan KJ, Gerber HP, Novotny W:Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004,3(5):391-400.
7. Ribatti D, Vacca A, Presta M:The discovery of angiogenic factors:a historical review. Gen Pharmacol 2000,35(5):227-231.
8. Carmeliet P, Jain RK:Angiogenesis in cancer and other diseases. Nature 2000, 407(6801):249-257.
9. Miller KD:Issues and challenges for antiangiogenic therapies. Breast Cancer Res Treat 2002,75 Suppl 1:S45-50; discussion S57-48.
10. BI Anding YL, YANG Jun, ZHANG Min, ZHOU Yi & ZHAO Shouyuan: Cloning and expression analysis of human reticulon 4c cDNA. Chinese Science Bulletin 2000,45:1862-1868.
11. Acevedo L, Yu J, Erdjument-Bromage H, Miao RQ, Kim JE, Fulton D, Tempst P, Strittmatter SM, Sessa WC:A new role for Nogo as a regulator of vascular remodeling. Nat Med 2004,10(4):382-388.
12. Pugh CW, Ratcliffe PJ:Regulation of angiogenesis by hypoxia:role of the HIF system. Nat Med 2003,9(6):677-684.
13. Guillemin K, Krasnow MA:The hypoxic response:huffing and HIFing. Cell 1997,89(1):9-12.
14. Beck I, Weinmann R, Caro J:Characterization of hypoxia-responsive enhancer in the human erythropoietin gene shows presence of hypoxia-inducible 120-Kd nuclear DNA-binding protein in erythropoietin-producing and nonproducing cells. Blood 1993,82(3):704-711.
15. Shaulian E, Karin M:AP-1 in cell proliferation and survival. Oncogens 2001, 20(19):2390-2400.
16. Halazonetis TD, Georgopoulos K, Greenberg ME, Leder P:c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities. Cell 1988,55(5):917-924.
17. Ryseck RP, Bravo R:c-JUN, JUN B, and JUN D differ in their binding affinities to AP-1 and CRE consensus sequences:effect of FOS proteins. Oncogene 1991,6(4):533-542.
18. van Dam H, Castellazzi M:Distinct roles of Jun:Fos and Jun:ATF dimers in oncogenesis. Oncogene 2001,20(19):2453-2464.
19. Shaulian E, Karin M:AP-1 as a regulator of cell life and death. Nat Cell Biol 2002,4(5):E131-136.
20. Jochum W, Passegue E, Wagner EF:AP-1 in mouse development and tumorigenesis. Oncogene 2001,20(19):2401-2412.
21. Hu E, Mueller E, Oliviero S, Papaioannou VE, Johnson R, Spiegelman BM: Targeted disruption of the c-fos gene demonstrates c-fos-dependent and-independent pathways for gene expression stimulated by growth factors or oncogenes. Embo J 1994,13(13):3094-3103.
22. Kustikova O, Kramerov D, Grigorian M, Berezin V, Bock E, Lukanidin E, Tulchinsky E:Fra-1 induces morphological transformation and increases in vitro invasiveness and motility of epithelioid adenocarcinoma cells. Mol Cell Biol 1998,18(12):7095-7105.
23. Marconcini L, Marchio S, Morbidelli L, Cartocci E, Albini A, Ziche M, Bussolino F, Oliviero S:c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro. Proc Natl Acad Sci USA 1999,96(17):9671-9676.
24. Toft DJ, Rosenberg SB, Bergers G, Volpert O, Linzer DI:Reactivation of proliferin gene expression is associated with increased angiogenesis in a cell culture model of fibrosarcoma tumor progression. Proc Natl Acad Sci U S A 2001,98(23):13055-13059.
25. Greenberg ME, Ziff EB:Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature 1984,311(5985):433-438.
26. Wang GL, Semenza GL:Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 1993, 268(29):21513-21518.
27. Pore N, Liu S, Shu HK, Li B, Haas-Kogan D, Stokoe D, Milanini-Mongiat J, Pages G, O'Rourke DM, Bernhard E et al:Spl is involved in Akt-mediated induction of VEGF expression through an HIF-1-independent mechanism. Mol Biol Cell 2004,15(11):4841-4853.
28. Yuen MF, Wu PC, Lai VC, Lau JY, Lai CL:Expression of c-Myc, c-Fos, and c-jun in hepatocellular carcinoma. Cancer 2001,91 (1):106-112.
29. Borlak J, Meier T, Halter R, Spanel R, Spanel-Borowski K:Epidermal growth factor-induced hepatocellular carcinoma:gene expression profiles in precursor lesions, early stage and solitary tumours. Oncogene 2005,24(11):1809-1819.
1. Rosenquist M, Alsterfjord M, Larsson C, Sommarin M:Data mining the Arabidopsis genome reveals fifteen 14-3-3 genes. Expression is demonstrated for two out of five novel genes. Plant Physiol 2001,127(1):142-149.
2. Wang W, Shakes DC:Molecular evolution of the 14-3-3 protein family. J Mol Evol 1996,43(4):384-398.
3. Moore BW, Perez VJ:Specific acidic proteins of the nervous system. In: Physiological and Biochemical Aspects of Nervous Integration. Edited by Carlson FD. Prentice-Hall, Englewood Cliffs, NJ; 1968:343-359.
4. Ichimura T, Isobe T, Okuyama T, Yamauchi T, Fujisawa H:Brain 14-3-3 protein is an activator protein that activates tryptophan 5-monooxygenase and tyrosine 3-monooxygenase in the presence of Ca2+,calmodulin-dependent protein kinase II. FEBS Lett 1987,219(l):79-82.
5. Toker A, Ellis CA, Sellers LA, Aitken A:Protein kinase C inhibitor proteins. Purification from sheep brain and sequence similarity to lipocortins and 14-3-3 protein. Eur J Biochem 1990,191(2):421-429.
6. Fantl WJ, Muslin AJ, Kikuchi A, Martin JA, MacNicol AM, Gross RW, Williams LT:Activation of Raf-1 by 14-3-3 proteins. Nature 1994, 371(6498):612-614.
7. Fu H, Xia K, Pallas DC, Cui C, Conroy K, Narsimhan RP, Mamon H, Collier RJ, Roberts TM:Interaction of the protein kinase Raf-1 with 14-3-3 proteins. Science 1994,266(5182):126-129.
8. Freed E, Symons M, Macdonald SQ McCormick F, Ruggieri R:Binding of 14-3-3 proteins to the protein kinase Raf and effects on its activation. Science 1994,265(5179):1713-1716.
9. Thorson JA, Yu LW, Hsu AL, Shih NY, Graves PR, Tanner JW, Allen PM, Piwnica-Worms H, Shaw AS:14-3-3 proteins are required for maintenance of Raf-1 phosphorylation and kinase activity. Mol Cell Biol 1998, 18(9):5229-5238.
10. Muslin AJ, Tanner JW, Allen PM, Shaw AS:Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell 1996, 84(6):889-897.
11. Xiao B, Smerdon SJ, Jones DH, Dodson GG, Soneji Y, Aitken A, Gamblin SJ: Structure of a 14-3-3 protein and implications for coordination of multiple signalling pathways. Nature 1995,376(6536):188-191.
12. Liu D, Bienkowska J, Petosa C, Collier RJ, Fu H, Liddington R:Crystal structure of the zeta isoform of the 14-3-3 protein. Nature 1995, 376(6536):191-194.
13. Luo ZJ, Zhang XF, Rapp U, Avruch J:Identification of the 14.3.3 zeta domains important for self-association and Raf binding. J Biol Chem 1995, 270(40):23681-23687.
14. Tzivion G, Luo Z, Avruch J:A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity. Nature 1998,394(6688):88-92.
15. Zhang L, Wang H, Liu D, Liddington R, Fu H:Raf-1 kinase and exoenzyme S interact with 14-3-3zeta through a common site involving lysine 49. J Biol Chem 1997,272(21):13717-13724.
16. Wang H, Zhang L, Liddington R, Fu H:Mutations in the hydrophobic surface of an amphipathic groove of 14-3-3zeta disrupt its interaction with Raf-1 kinase. J Biol Chem 1998,273(26):16297-16304.
17. Rittinger K, Budman J, Xu J, Volinia S, Cantley LC, Smerdon SJ, Gamblin SJ, Yaffe MB:Structural analysis of 14-3-3 phosphopeptide complexes identifies a dual role for the nuclear export signal of 14-3-3 in ligand binding. Mol Cell 1999,4(2):153-166.
18. Roseboom PH, Weller JL, Babila T, Aitken A, Sellers LA, Moffett JR, Namboodiri MA, Klein DC:Cloning and characterization of the epsilon and zeta isoforms of the 14-3-3 proteins. DNA Cell Biol 1994,13(6):629-640.
19. Cardoso C, Leventer RJ, Ward HL, Toyo-Oka K, Chung J, Gross A, Martin CL, Allanson J, Pilz DT, Olney AH et at Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 2003,72(4):918-930.
20. Wiltfang J, Otto M, Baxter HC, Bodemer M, Steinacker P, Bahn E, Zerr I, Kornhuber J, Kretzschmar HA, Poser S el al: Isoform pattern of 14-3-3 proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. J Neurochem 1999,73(6):2485-2490.
21. Fountoulakis M, Cairns N, Lubec G:Increased levels of 14-3-3 gamma and epsilon proteins in brain of patients with Alzheimer's disease and Down syndrome. J Neural Transm Suppl 1999,57:323-335.
22. Oriente F, Andreozzi F, Romano C, Perruolo G, Perfetti A, Fiory F, Miele C, Beguinot F, Formisano P:Protein kinase C-alpha regulates insulin action and degradation by interacting with insulin receptor substrate-1 and 14-3-3 epsilon. JBiol Chem 2005,280(49):40642-40649.
23. Chang HC, Rubin GM:14-3-3 epsilon positively regulates Ras-mediated signaling in Drosophila. Genes Dev 1997,11 (9):1132-1139.
24. Gu M, Du X:A novel ligand-binding site in the zeta-form 14-3-3 protein recognizing the platelet glycoprotein Ibalpha and distinct from the c-Raf-binding site. J Biol Chem 1998,273(50):33465-33471.
25. Zhou Y, Reddy S, Murrey H, Fei H, Levitan IB:Monomeric 14-3-3 protein is sufficient to modulate the activity of the Drosophila slowpoke calcium-dependent potassium channel. J Biol Chem 2003, 278(12):10073-10080.
26. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG:The CLUSTAL_X windows interface:flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 1997, 25(24):4876-4882.
27. Yang X, Lee WH, Sobott F, Papagrigoriou E, Robinson CV, Grossmann JG, Sundstrom M, Doyle DA, Elkins JM:Structural basis for protein-protein interactions in the 14-3-3 protein family. Proc Natl Acad Sci USA 2006, 103(46):17237-17242.
1. Folkman J:Tumor angiogenesis:therapeutic implications. N Engl J Med 1971, 285(21):1182-1186.
2. Gimbrone MA, Jr., Leapman SB, Cotran RS, Folkman J:Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 1972,136(2):261-276.
3. Brem S, Brem H, Folkman J, Finkelstein D, Patz A:Prolonged tumor dormancy by prevention of neovascularization in the vitreous. Cancer Res 1976,36(8):2807-2812.
4. Parangi S, O'Reilly M, Christofori G, Holmgren L, Grosfeld J, Folkman J, Hanahan D:Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proc Natl Acad Sci USA 1996,93(5):2002-2007.
5. Holmgren L, O'Reilly MS, Folkman J:Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995,1(2):149-153.
6. Carmeliet P:Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000, 6(4):389-395.
7. Bergers G, Benjamin LE:Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003,3(6):401-410.
8. Naumov GN, Akslen LA, Folkman J:Role of angiogenesis in human tumor dormancy:animal models of the angiogenic switch. Cell Cycle 2006, 5(16):1779-1787.
9. Folkman J, Watson K, Ingber D, Hanahan D:Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989,339(6219):58-61.
10. North S, Moenner M, Bikfalvi A:Recent developments in the regulation of the angiogenic switch by cellular stress factors in tumors. Cancer Lett 2005, 218(1):1-14.
11. Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, Pollard JW:Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 2006,66(23):11238-11246.
12. Nozawa H, Chiu C, Hanahan D:Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A 2006,103(33):12493-12498.
13. Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ:Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999, 284(5422):1994-1998.
14. Giordano FJ, Johnson RS:Angiogenesis:the role of the microenvironment in flipping the switch. Curr Opin Genet Dev2001, 11(1):35-40.
15. Hockel M, Vaupel P:Tumor hypoxia:definitions and current clinical, biologic, and molecular aspects. JNatl Cancer Inst 2001,93(4):266-276.
16. Hockel M, Schlenger K, Hockel S, Vaupel P:Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res 1999, 59(18):4525-4528.
17. Semenza GL:Hydroxylation of HIF-1:oxygen sensing at the molecular level. Physiology (Bethesda) 2004,19:176-182.
18. Peng J, Zhang L, Drysdale L, Fong GH:The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Proc Natl Acad Sci U S A 2000,97(15):8386-8391.
19. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y:A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor lalpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A 1997, 94(9):4273-4278.
20. Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L:Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 2001, 414(6863):550-554.
21. Carrero P, Okamoto K, Coumailleau P, O'Brien S, Tanaka H, Poellinger L: Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor lalpha. Mol Cell Biol 2000, 20(1):402-415.
22. Lando D, Pongratz I, Poellinger L, Whitelaw ML:A redox mechanism controls differential DNA binding activities of hypoxia-inducible factor (HIF) 1 alpha and the HIF-like factor. J Biol Chem 2000,275(7):4618-4627.
23. Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH:Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. JBiol Chem 2000,275(33):25733-25741.
24. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG:Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000,2(7):423-427.
25. Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW: Activation of HIFl alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci U S A 2000, 97(19):10430-10435.
26. Tanimoto K, Makino Y, Pereira T, Poellinger L:Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. Embo J 2000,19(16):4298-4309.
27. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ:The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999,399(6733):271-275.
28. Stebbins CE, Kaelin WG, Jr., Pavletich NP:Structure of the VHL-ElonginC-ElonginB complex:implications for VHL tumor suppressor function. Science 1999,284(5413):455-461.
29. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ et al: Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001,292(5516):468-472.
30. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG, Jr.:HIFalpha targeted for VHL-mediated destruction by proline hydroxylation:implications for 02 sensing. Science 2001, 292(5516):464-468.
31. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ:Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. Embo J 2001,20(18):5197-5206.
32. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT:Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-lalpha during hypoxia:a mechanism of 02 sensing. J Biol Chem 2000, 275(33):25130-25138.
33. Srinivas V, Leshchinsky I, Sang N, King MP, Minchenko A, Caro J:Oxygen sensing and HIF-1 activation does not require an active mitochondrial respiratory chain electron-transfer pathway. J Biol Chem 2001, 276(25):21995-21998.
34. Vaux EC, Metzen E, Yeates KM, Ratcliffe PJ:Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain. Blood 2001,98(2):296-302.
35. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A et al:C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001,107(1):43-54.
36. Bruick RK, McKnight SL:A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001,294(5545):1337-1340.
37. Mahon PC, Hirota K, Semenza GL:FIH-1:a novel protein that interacts with HIF-lalpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 2001,15(20):2675-2686.
38. Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK:FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 2002,16(12):1466-1471.
39. Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM:An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci USA 1996,93(23):12969-12973.
40. Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J:p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor lalpha (HIF-lalpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 1999,274(46):32631-32637.
41. Mylonis I, Chachami G, Samiotaki M, Panayotou G, Paraskeva E, Kalousi A, Georgatsou E, Bonanou S, Simos G:Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1 alpha. J Biol Chem 2006,281(44):33095-33106.
42. Shaw RJ, Cantley LC:Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006,441(7092):424-430.
43. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL:Modulation of hypoxia-inducible factor lalpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AK.T/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000, 60(6):1541-1545.
44. Blancher C, Moore JW, Robertson N, Harris AL:Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-lalpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway. Cancer Res 2001,61(19):7349-7355.
45. Poulaki V, Mitsiades CS, McMullan C, Sykoutri D, Fanourakis G, Kotoula V, Tseleni-Balafouta S, Koutras DA, Mitsiades N:Regulation of vascular endothelial growth factor expression by insulin-like growth factor I in thyroid carcinomas.J Clin Endocrinol Metab 2003,88(11):5392-5398.
46. Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB et al:Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 2000,14(4):391-396.
47. Grunstein J, Masbad JJ, Hickey R, Giordano F, Johnson RS:Isoforms of vascular endothelial growth factor act in a coordinate fashion To recruit and expand tumor vasculature. Mol Cell Biol 2000,20(19):7282-7291.
48. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 1996,16(9):4604-4613.
49. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L:VEGF receptor signalling-in control of vascular function. Nat Rev Mol Cell Biol 2006, 7(5):359-371.
50. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, Powell-Braxton L, Hillan KJ, Moore MW:Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996, 380(6573):439-442.
51. Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D, Johnson RS: Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res 1999, 59(7):1592-1598.
52. Jensen RL, Ragel BT, Whang K, Gillespie D:Inhibition of hypoxia inducible factor-lalpha (HIF-lalpha) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in malignant gliomas. J Neurooncol 2006, 78(3):233-247.
53. Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, van Diest PJ, van der Wall E:Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 2001,93(4):309-314.
54. Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW, Ratcliffe PJ:Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 1997,94(15):8104-8109.
55. Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP, Ferrara N, Johnson RS:Loss of HIF-1 alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 2004, 6(5):485-495.
56. Das B, Yeger H, Tsuchida R, Torkin R, Gee MF, Thorner PS, Shibuya M, Malkin D, Baruchel S:A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxia-inducible factor-1 alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. Cancer Res 2005,65(16):7267-7275.
57. Morbidelli L, Donnini S, Ziche M:Role of nitric oxide in the modulation of angiogenesis. Curr Pharm Des 2003,9(7):521-530.
58. Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura T, D'Acquisto F, Addeo R, Makuuchi M, Esumi H:Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide:control of hypoxia-inducible factor-1 activity by nitric oxide. ,95(1):189-197.
59. Palmer LA, Semenza GL, Stoler MH, Johns RA:Hypoxia induces type Ⅱ NOS gene expression in pulmonary artery endothelial cells via HIF-1. Am J Physiol 1998,274(2 Pt 1):L212-219.
60. Jung F, Palmer LA, Zhou N, Johns RA:Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes. Circ Res 2000,86(3):319-325.
61. Coulet F, Nadaud S, Agrapart M, Soubrier F:Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter. J Biol Chem 2003,278(47):46230-46240.
62. Cooke JP:NO and angiogenesis. Atheroscler Suppl 2003,4(4):53-60.
63. Rossig L, Fichtlscherer B, Breitschopf K, Haendeler J, Zeiher AM, Mulsch A, Dimmeler S:Nitric oxide inhibits caspase-3 by S-nitrosation in vivo. J Biol Chem 1999,274(11):6823-6826.
64. Ellies LG, Fishman M, Hardison J, Kleeman J, Maglione JE, Manner CK, Cardiff RD, MacLeod CL:Mammary tumor latency is increased in mice lacking the inducible nitric oxide synthase. Int J Cancer 2003,106(1):1-7.
65. Cullis ER, Kalber TL, Ashton SE, Cartwright JE, Griffiths JR, Ryan AJ, Robinson SP:Tumour overexpression of inducible nitric oxide synthase (iNOS) increases angiogenesis and may modulate the anti-tumour effects of the vascular disrupting agent ZD6126. Microvasc Res 2006,71(2):76-84.
66. Grose R, Dickson C:Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev 2005,16(2):179-186.
67. Shi YH, Wang YX, Bingle L, Gong LH, Heng WJ, Li Y, Fang WG:In vitro study of HIF-1 activation and VEGF release by bFGF in the T47D breast cancer cell line under normoxic conditions:involvement of PI-3K/Akt and MEK1/ERK pathways. J Pathol 2005,205(4):530-536.
68. Pore N, Liu S, Haas-Kogan DA, O'Rourke DM, Maity A:PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. Cancer Res 2003, 63(1):236-241.
69. Calvani M, Rapisarda A, Uranchimeg B, Shoemaker RH, Melillo G:Hypoxic induction of an HIF-1 alpha-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells. Blood 2006,107(7):2705-2712.
70. Li J, Shworak NW, Simons M:Increased responsiveness of hypoxic endothelial cells to FGF2 is mediated by HIF-1 alpha-dependent regulation of enzymes involved in synthesis of heparan sulfate FGF2-binding sites.J Cell Sci 2002,115(Pt9):1951-1959.
71. Brat DJ, Mapstone TB:Malignant glioma physiology:cellular response to hypoxia and its role in tumor progression. Ann Intern Med 2003, 138(8):659-668.
72. Arteaga CL:Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 2002,7 Suppl 4:31-39.
73. Ueda S, Basaki Y, Yoshie M, Ogawa K, Sakisaka S, Kuwano M, Ono M: PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib. Cancer Res 2006,66(10):5346-5353.
74. Lederle W, Stark HJ, Skobe M, Fusenig NE, Mueller MM:Platelet-derived growth factor-BB controls epithelial tumor phenotype by differential growth factor regulation in stromal cells. Am JPathol 2006,169(5):1767-1783.
75. Nakamura K, Taguchi E, Miura T, Yamamoto A, Takahashi K, Bichat F, Guilbaud N, Hasegawa K, Kubo K, Fujiwara Y et al: KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res 2006,66(18):9134-9142.
76. Mizukami Y, Li J, Zhang X, Zimmer MA, Iliopoulos O, Chung DC: Hypoxia-inducible factor-1-independent regulation of vascular endothelial growth factor by hypoxia in colon cancer. Cancer Res 2004,64(5):1765-1772.
77. Mizukami Y, Fujiki K, Duerr EM, Gala M, Jo WS, Zhang X, Chung DC: Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc.J Biol Chem 2006,281(20):13957-13963.
78. Jin HG, Yamashita H, Nagano Y, Fukuba H, Hiji M, Ohtsuki T, Takahashi T, Kohriyama T, Kaibuchi K, Matsumoto M:Hypoxia-induced upregulation of endothelial small G protein RhoA and Rho-kinase/ROCK2 inhibits eNOS expression. NeurosciLett 2006,408(1):62-67.
79. Chandel NS, Trzyna WC, McClintock DS, Schumacker PT:Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin. J Immunol 2000,165(2):1013-1021.
80. Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, Godson C, Nielsen JE, Moynagh P, Pouyssegur J et al: Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci U S A 2006, 103(48):18154-18159.
81. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB: NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 1999,401(6748):82-85.
82. Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ:Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res 2000,60(19):5334-5339.
83. Fujioka S, Sclabas GM, Schmidt C, Niu J, Frederick WA, Dong QG, Abbruzzese JL, Evans DB, Baker C, Chiao PJ:Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses tumorigenesis. Oncogene 2003,22(9):1365-1370.
84. Kiriakidis S, Andreakos E, Monaco C, Foxwell B, Feldmann M, Paleolog E: VEGF expression in human macrophages is NF-kappaB-dependent:studies using adenoviruses expressing the endogenous NF-kappaB inhibitor IkappaBalpha and a kinase-defective form of the IkappaB kinase 2.J Cell Sci 2003,116(Pt 4):665-674.
85. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA:The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991, 266(18):11947-11954.
86. Fujioka S, Niu J, Schmidt C, Sclabas GM, Peng B, Uwagawa T, Li Z, Evans DB, Abbruzzese JL, Chiao PJ:NF-kappaB and AP-1 connection:mechanism of NF-kappaB-dependent regulation of AP-1 activity. Mol Cell Biol 2004, 24(17):7806-7819.
87. Salnikow K, Kluz T, Costa M, Piquemal D, Demidenko ZN, Xie K, Blagosklonny MV:The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia. Mol Cell Biol 2002,22(6):1734-1741.
88. Jung YJ, Isaacs JS, Lee S, Trepel J, Neckers L:IL-1 beta-mediated up-regulation of HIF-1 alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. Faseb J 2003, 17(14):2115-2117.
89. Bonello S, Zahringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, Kietzmann T, Gorlach A:Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arterioscler Thromb Vasc Biol 2007, 27(4):755-761.