PP2A抑制剂对胰腺癌细胞生长、转移的抑制作用及机制研究
|
摘要
目的:斑蝥素(Cantharidin)是传统抗癌中药斑蝥的活性成分,并且是蛋白磷酸酶2A(protein phosphatase 2A,PP2A)的选择性抑制剂。鉴于Cantharidin的抗癌作用,我们拟探讨Cantharidin在胰腺癌治疗中的应用价值。
方法:通过MTT检测PP2A抑制剂Cantharidin和冈田酸(Okadaic acid,OA)对细胞增殖能力的影响;通过PP2A活性检测试剂盒检测Cantharidin对PP2A活性的抑制作用;通过平板克隆形成实验检测Cantharidin对胰腺癌细胞克隆形成能力的影响;通过流式细胞术检测Cantharidin对胰腺癌细胞细胞周期和凋亡的影响;通过Caspase活性检测试剂盒检测Cantharidin对外源性和内源性凋亡通路的激活作用;通过RT-PCR,Western blot检测Cantharidin对周期和凋亡相关基因表达的调控;通过流式细胞术检测Cantharidin诱导氧化应激的产生,并通过MTT检测Cantharidin诱导的氧化应激对胰腺癌细胞增殖能力的影响;通过划痕实验和transwell迁移实验检测Cantharidin对胰腺癌细胞迁移能力的影响;通过transwell侵袭实验检测Cantharidin对胰腺癌细胞侵袭能力的影响;通过RT-PCR检测Cantharidin对胰腺癌细胞基质金属蛋白酶-2(MMP-2)mRNA表达的影响;通过酶谱法检测Cantharidin对胰腺癌细胞MMP-2分泌量的影响。
结果:Cantharidin可显著抑制胰腺癌细胞增殖能力,而对正常胰腺导管上皮细胞的毒性相对较弱。Cantharidin显著抑制PP2A活性,另一PP2A经典抑制剂OA也对胰腺癌细胞有显著抑制作用,提示Cantharidin对胰腺癌细胞的毒性作用可能是通过抑制PP2A活性。Cantharidin显著抑制细胞周期,呈G2/M期阻滞,并可诱导细胞凋亡。内源性和外源性凋亡通路均被激活。与G2/M期调控相关的CDK1表达下调,p21表达上调。促凋亡基因TNF-α, TRAILR1, TRAILR2, Bad, Bak和Bid表达增加,抗凋亡基因Bcl-2表达减少。Cantharidin可诱导显著的氧化应激,但Cantharidin所产生的氧化应激并不能抑制细胞生长。Cantharidin显著抑制胰腺癌细胞的迁移和侵袭能力,并显著抑制MMP-2表达和分泌。
结论:研究结果显示Cantharidin对胰腺癌细胞的生长和转移具有显著的抑制作用,有望成为胰腺癌的有效治疗药物,PP2A有可能成为胰腺癌治疗靶点。
目的:蛋白磷酸酶PP2A(protein phosphatase 2A)可以使诸多激酶去磷酸化而失活,由于激酶通路的激活通常会促进肿瘤细胞生长,因此PP2A被认为是抑癌因子,而PP2A抑制剂被认为是诱癌剂。然而,我们在第一部分研究中发现,PP2A抑制剂斑蝥素(Cantharidin)和冈田酸(Okadaic acid, OA)对胰腺癌细胞的生长有显著抑制作用,具体机制尚不清楚。IKK (IκB kinase)是NF-κB信号通路的上游激酶,PP2A可使IKK去磷酸化而失活,PP2A抑制剂可促进IKK磷酸化而激活NF-κB通路。激活NF-κB通路在某些情况下可诱导凋亡,因此,在本部分研究中,我们拟验证PP2A抑制剂对胰腺癌细胞的凋亡诱导作用是否是通过激活NF-κB通路。
方法:通过MTT检测PP2A抑制剂对胰腺癌细胞活力的影响;通过流式细胞术检测PP2A抑制剂对胰腺癌细胞细胞凋亡的影响;通过RT-PCR和Western blot检测基因表达水平;通过Western blot和荧光素酶报告基因检测PP2A抑制剂对NF-κB通路的激活作用;通过Caspase活性检测试剂盒检测PP2A抑制剂对外源性和内源性凋亡通路的激活作用。
结果:PP2A抑制剂Cantharidin和OA可导致IKKα持续磷酸化、IκBα磷酸化和降解,以及p65入核,提示PP2A抑制剂可激活胰腺癌细胞NF-?B通路。分别用DN-IKKα(IKKα显性负性突变体)、DN-IκBα(IκBα显性负性突变体)、Bay 11-7082(IκBα磷酸化抑制剂)、p65-shRNA阻断NF-?B通路,削弱了PP2A抑制剂对胰腺癌细胞活力的抑制作用,说明PP2A抑制剂抑制胰腺癌细胞活力是通过NF-?B通路依赖性途径。进一步我们研究发现,PP2A抑制剂通过激活NF-?B通路诱导了胰腺癌细胞通过外源性凋亡途径凋亡。同时PP2A抑制剂通过激活NF-?B通路选择性地促进了参与外源性凋亡途径的下游基因TNF-α, TRAILR1、TRAILR2的表达。另外,我们发现虽然PP2A抑制剂导致的NF-κB通路的持续激活可诱导胰腺癌细胞凋亡,NF-κB通路的基础活性却对维持细胞生存有重要作用,抑制NF-κB通路的基础活性也可诱导胰腺癌细胞凋亡。
结论:PP2A抑制剂通过NF-κB通路依赖性途径诱导胰腺癌细胞凋亡。PP2A是潜在的胰腺癌治疗靶点。
Objective: Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. It is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in control of cell cycle, apoptosis, and cell-fate determination. Owing to its antitumor activity, Cantharidin has been frequently used in clinical practice. In the present study, we investigated the therapeutic potential of Cantharidin in pancreatic cancer.
Methods: Proliferation was determined by MTT. The activity of PP2A was analyzed by using the nonradioactive serine/threonine-phosphatase assay kit. Clone formation ability was determined by flat plate clone formation assay. Cell cycle, apoptosis and oxidative stress were tested by flow cytometry. Caspase activity was measured using commercial kits. Gene expressions were tested using RT-PCR and Western blot. Migration was assayed by wound healing assay and transwell. Invasion was assessed by transwell. The expression and secretion level of matrix metalloproteinase-2 (MMP-2) was determined by RT-PCR and zymography repectively.
Results: Cantharidin efficiently inhibited the growth of pancreatic cancer cells, but presented much lighter toxicity effect against normal pancreatic duct cells. Cantharidin inhibited the activity of PP2A. Okadaic acid (OA), a classical PP2A inhibitor, also presented inhibition on the growth of pancreatic cancer cells, suggesting the anti-cancer effect of Cantharidin is probably due to the inhibition of PP2A. Cantharidin caused G2/M cell-cycle arrest that was accompanied by the down-regulation of CDK1 and up-regulation of p21 expression. It induced apoptosis and elevated the expressions of pro-apoptotic factors, TNF-α, TRAILR1, TRAILR2, Bad, Bak, and Bid, and decreased the expression of anti-apoptotic Bcl-2. Activation of Caspase 8 and Caspase 9 suggested that both extrinsic and intrinsic pathways are involved in the induction of apoptosis. Interestingly, unlike previous studies on other cancer cells, we found that the inhibitory role of Cantharidin is independent of oxidative stress in pancreatic cancer cells. Cantharidin significantly inhibited the migration and invasion ability of pancreatic cancer cells and repressed the expression and secretion of MMP-2.
Conclusion: In addition to being an attractive candidate compound with therapeutic potential, Cantharidin also highlighted the possibility of using PP2A as a therapeutic target for pancreatic cancer treatment.
Objective: PP2A (protein phosphatase 2A) is a multimeric serine/threonine phosphatase which can dephosphorylate multiple kinases. It is thought to be a cancer suppresser, as inhibition of PP2A can induce phosphorylation and activation of substrate kinases, most of which can further accelerate growth. Interestingly, we have found that PP2A inhibitors, Cantharidin and Okadaic acid (OA), inhibited pancreatic cancer cell growth, although the mechanism involved is still unclear. IKK (IκB kinase), the key regulator of NF-κB pathway, is a direct substrate of PP2A. As activation of NF-κB pathway can trigger apoptosis in some circumstance, we tried to investigate whether PP2A inhibitors could induce apoptosis in pancreatic cancer cells through activation of NF-κB pathway.
Methods: Proliferation was determined by MTT. Apoptosis was tested by flow cytometry. Gene expressions were tested using RT-PCR and Western blot. Activation of NF-κB pathway was measured using Western blot and luciferase reporter gene assay. Caspase activity was measured using commercial kits.
Results: Treatment with PP2A inhibitors induced activation of NF-κB pathway through phosphorylation of IKKα, phosphorylation and degradation of IκBα, and nuclear translocation of p65. Using dominant negative -IKKα, dominant negative -IκBα, Bay 11-7082 (an inhibitor of IκBαphosphorylation) or p65 specific shRNA, we could not only block the activation of NF-κB pathway, but also attenuate the cytotoxicity of PP2A inhibitors, suggesting the anti-cancer effect of PP2A inhibitors is executed in a NF-κB pathway dependent manner. We further find out that the transcriptional activation of NF-κB pathway increased the expression of downstream pro-apoptotic genes, TNF-α, TRAILR1, and TRAILR2, and triggered apoptosis through the extrinsic pathway. Interestingly, although the PP2A inhibitors-induced excessive activation of NF-κB presented to be cytotoxic, we also found that the basal activity of this pathway is critical to the survival of pancreatic cancer cells.
Conclusion: We provided convincing evidence that PP2A inhibitors induced cytotoxic effects against pancreatic cancer cells through persistent activation of the NF-κB pathway, indicating that PP2A is a potential target for pancreatic cancer treatment.
方法:通过MTT检测PP2A抑制剂Cantharidin和冈田酸(Okadaic acid,OA)对细胞增殖能力的影响;通过PP2A活性检测试剂盒检测Cantharidin对PP2A活性的抑制作用;通过平板克隆形成实验检测Cantharidin对胰腺癌细胞克隆形成能力的影响;通过流式细胞术检测Cantharidin对胰腺癌细胞细胞周期和凋亡的影响;通过Caspase活性检测试剂盒检测Cantharidin对外源性和内源性凋亡通路的激活作用;通过RT-PCR,Western blot检测Cantharidin对周期和凋亡相关基因表达的调控;通过流式细胞术检测Cantharidin诱导氧化应激的产生,并通过MTT检测Cantharidin诱导的氧化应激对胰腺癌细胞增殖能力的影响;通过划痕实验和transwell迁移实验检测Cantharidin对胰腺癌细胞迁移能力的影响;通过transwell侵袭实验检测Cantharidin对胰腺癌细胞侵袭能力的影响;通过RT-PCR检测Cantharidin对胰腺癌细胞基质金属蛋白酶-2(MMP-2)mRNA表达的影响;通过酶谱法检测Cantharidin对胰腺癌细胞MMP-2分泌量的影响。
结果:Cantharidin可显著抑制胰腺癌细胞增殖能力,而对正常胰腺导管上皮细胞的毒性相对较弱。Cantharidin显著抑制PP2A活性,另一PP2A经典抑制剂OA也对胰腺癌细胞有显著抑制作用,提示Cantharidin对胰腺癌细胞的毒性作用可能是通过抑制PP2A活性。Cantharidin显著抑制细胞周期,呈G2/M期阻滞,并可诱导细胞凋亡。内源性和外源性凋亡通路均被激活。与G2/M期调控相关的CDK1表达下调,p21表达上调。促凋亡基因TNF-α, TRAILR1, TRAILR2, Bad, Bak和Bid表达增加,抗凋亡基因Bcl-2表达减少。Cantharidin可诱导显著的氧化应激,但Cantharidin所产生的氧化应激并不能抑制细胞生长。Cantharidin显著抑制胰腺癌细胞的迁移和侵袭能力,并显著抑制MMP-2表达和分泌。
结论:研究结果显示Cantharidin对胰腺癌细胞的生长和转移具有显著的抑制作用,有望成为胰腺癌的有效治疗药物,PP2A有可能成为胰腺癌治疗靶点。
目的:蛋白磷酸酶PP2A(protein phosphatase 2A)可以使诸多激酶去磷酸化而失活,由于激酶通路的激活通常会促进肿瘤细胞生长,因此PP2A被认为是抑癌因子,而PP2A抑制剂被认为是诱癌剂。然而,我们在第一部分研究中发现,PP2A抑制剂斑蝥素(Cantharidin)和冈田酸(Okadaic acid, OA)对胰腺癌细胞的生长有显著抑制作用,具体机制尚不清楚。IKK (IκB kinase)是NF-κB信号通路的上游激酶,PP2A可使IKK去磷酸化而失活,PP2A抑制剂可促进IKK磷酸化而激活NF-κB通路。激活NF-κB通路在某些情况下可诱导凋亡,因此,在本部分研究中,我们拟验证PP2A抑制剂对胰腺癌细胞的凋亡诱导作用是否是通过激活NF-κB通路。
方法:通过MTT检测PP2A抑制剂对胰腺癌细胞活力的影响;通过流式细胞术检测PP2A抑制剂对胰腺癌细胞细胞凋亡的影响;通过RT-PCR和Western blot检测基因表达水平;通过Western blot和荧光素酶报告基因检测PP2A抑制剂对NF-κB通路的激活作用;通过Caspase活性检测试剂盒检测PP2A抑制剂对外源性和内源性凋亡通路的激活作用。
结果:PP2A抑制剂Cantharidin和OA可导致IKKα持续磷酸化、IκBα磷酸化和降解,以及p65入核,提示PP2A抑制剂可激活胰腺癌细胞NF-?B通路。分别用DN-IKKα(IKKα显性负性突变体)、DN-IκBα(IκBα显性负性突变体)、Bay 11-7082(IκBα磷酸化抑制剂)、p65-shRNA阻断NF-?B通路,削弱了PP2A抑制剂对胰腺癌细胞活力的抑制作用,说明PP2A抑制剂抑制胰腺癌细胞活力是通过NF-?B通路依赖性途径。进一步我们研究发现,PP2A抑制剂通过激活NF-?B通路诱导了胰腺癌细胞通过外源性凋亡途径凋亡。同时PP2A抑制剂通过激活NF-?B通路选择性地促进了参与外源性凋亡途径的下游基因TNF-α, TRAILR1、TRAILR2的表达。另外,我们发现虽然PP2A抑制剂导致的NF-κB通路的持续激活可诱导胰腺癌细胞凋亡,NF-κB通路的基础活性却对维持细胞生存有重要作用,抑制NF-κB通路的基础活性也可诱导胰腺癌细胞凋亡。
结论:PP2A抑制剂通过NF-κB通路依赖性途径诱导胰腺癌细胞凋亡。PP2A是潜在的胰腺癌治疗靶点。
Objective: Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. It is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in control of cell cycle, apoptosis, and cell-fate determination. Owing to its antitumor activity, Cantharidin has been frequently used in clinical practice. In the present study, we investigated the therapeutic potential of Cantharidin in pancreatic cancer.
Methods: Proliferation was determined by MTT. The activity of PP2A was analyzed by using the nonradioactive serine/threonine-phosphatase assay kit. Clone formation ability was determined by flat plate clone formation assay. Cell cycle, apoptosis and oxidative stress were tested by flow cytometry. Caspase activity was measured using commercial kits. Gene expressions were tested using RT-PCR and Western blot. Migration was assayed by wound healing assay and transwell. Invasion was assessed by transwell. The expression and secretion level of matrix metalloproteinase-2 (MMP-2) was determined by RT-PCR and zymography repectively.
Results: Cantharidin efficiently inhibited the growth of pancreatic cancer cells, but presented much lighter toxicity effect against normal pancreatic duct cells. Cantharidin inhibited the activity of PP2A. Okadaic acid (OA), a classical PP2A inhibitor, also presented inhibition on the growth of pancreatic cancer cells, suggesting the anti-cancer effect of Cantharidin is probably due to the inhibition of PP2A. Cantharidin caused G2/M cell-cycle arrest that was accompanied by the down-regulation of CDK1 and up-regulation of p21 expression. It induced apoptosis and elevated the expressions of pro-apoptotic factors, TNF-α, TRAILR1, TRAILR2, Bad, Bak, and Bid, and decreased the expression of anti-apoptotic Bcl-2. Activation of Caspase 8 and Caspase 9 suggested that both extrinsic and intrinsic pathways are involved in the induction of apoptosis. Interestingly, unlike previous studies on other cancer cells, we found that the inhibitory role of Cantharidin is independent of oxidative stress in pancreatic cancer cells. Cantharidin significantly inhibited the migration and invasion ability of pancreatic cancer cells and repressed the expression and secretion of MMP-2.
Conclusion: In addition to being an attractive candidate compound with therapeutic potential, Cantharidin also highlighted the possibility of using PP2A as a therapeutic target for pancreatic cancer treatment.
Objective: PP2A (protein phosphatase 2A) is a multimeric serine/threonine phosphatase which can dephosphorylate multiple kinases. It is thought to be a cancer suppresser, as inhibition of PP2A can induce phosphorylation and activation of substrate kinases, most of which can further accelerate growth. Interestingly, we have found that PP2A inhibitors, Cantharidin and Okadaic acid (OA), inhibited pancreatic cancer cell growth, although the mechanism involved is still unclear. IKK (IκB kinase), the key regulator of NF-κB pathway, is a direct substrate of PP2A. As activation of NF-κB pathway can trigger apoptosis in some circumstance, we tried to investigate whether PP2A inhibitors could induce apoptosis in pancreatic cancer cells through activation of NF-κB pathway.
Methods: Proliferation was determined by MTT. Apoptosis was tested by flow cytometry. Gene expressions were tested using RT-PCR and Western blot. Activation of NF-κB pathway was measured using Western blot and luciferase reporter gene assay. Caspase activity was measured using commercial kits.
Results: Treatment with PP2A inhibitors induced activation of NF-κB pathway through phosphorylation of IKKα, phosphorylation and degradation of IκBα, and nuclear translocation of p65. Using dominant negative -IKKα, dominant negative -IκBα, Bay 11-7082 (an inhibitor of IκBαphosphorylation) or p65 specific shRNA, we could not only block the activation of NF-κB pathway, but also attenuate the cytotoxicity of PP2A inhibitors, suggesting the anti-cancer effect of PP2A inhibitors is executed in a NF-κB pathway dependent manner. We further find out that the transcriptional activation of NF-κB pathway increased the expression of downstream pro-apoptotic genes, TNF-α, TRAILR1, and TRAILR2, and triggered apoptosis through the extrinsic pathway. Interestingly, although the PP2A inhibitors-induced excessive activation of NF-κB presented to be cytotoxic, we also found that the basal activity of this pathway is critical to the survival of pancreatic cancer cells.
Conclusion: We provided convincing evidence that PP2A inhibitors induced cytotoxic effects against pancreatic cancer cells through persistent activation of the NF-κB pathway, indicating that PP2A is a potential target for pancreatic cancer treatment.
引文
.1. Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001;358:1576-85.
2. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet 2004;363:1049-57.
3. Guo X, Cui Z. Current diagnosis and treatment of pancreatic cancer in China. Pancreas 2005;31:13-22.
4. Danovi SA, Wong HH, Lemoine NR. Targeted therapies for pancreatic cancer. Br Med Bull 2008;87:97-130.
5. Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer 2002;2:897-909.
6. Wang GS. Medical uses of mylabris in ancient China and recent studies. J Ethnopharmacol 1989;26:147-62.
7. Honkanen RE. Cantharidin, another natural toxin that inhibits the activity of serine/threonine protein phosphatases types 1 and 2A. FEBS Lett 1993;330:283-6.
8. Huh JE, Kang KS, Chae C, Kim HM, Ahn KS, Kim SH. Roles of p38 and JNK mitogen-activated protein kinase pathways during Cantharidin-induced apoptosis in U937 cells. Biochem Pharmacol 2004;67:1811-8.
9. Chen YN, Chen JC, Yin SC, Wang GS, Tsauer W, Hsu SF, Hsu SL. Effector mechanisms of norCantharidin-induced mitotic arrest and apoptosis in human hepatoma cells. Int J Cancer 2002;100:158-65.
10. Fan YZ, Fu JY, Zhao ZM, Chen CQ. Inhibitory effect of norCantharidin on the growth of human gallbladder carcinoma GBC-SD cells in vitro. Hepatobiliary Pancreat Dis Int 2007;6:72-80.
11. Peng F, Wei YQ, Tian L, Yang L, Zhao X, Lu Y, Mao YQ, Kan B, Lei S, Wang GS, Jiang Y, Wang QR, et al. Induction of apoptosis by norCantharidin in human colorectal carcinoma cell lines: involvement of the CD95 receptor/ligand. J Cancer Res Clin Oncol 2002;128:223-30.
12. Huan SK, Lee HH, Liu DZ, Wu CC, Wang CC. Cantharidin-induced cytotoxicity and cyclooxygenase 2 expression in human bladder carcinoma cell line. Toxicology 2006;223:136-43.
13. Schafer KA. The cell cycle: a review. Vet Pathol 1998;35:461-78.
14. van den Heuvel S. Cell-cycle regulation. WormBook 2005:1-16.
15. Riedl SJ, Shi Y. Molecular mechanisms of Caspase regulation during apoptosis. Nat Rev Mol Cell Biol 2004;5:897-907.
16. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008;9:47-59.
17. Joyce D, Albanese C, Steer J, Fu M, Bouzahzah B, Pestell RG. NF-kappaB and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev 2001;12:73-90.
18. Stark GR, Taylor WR. Control of the G2/M transition. Mol Biotechnol 2006;32:227-48.
19. Fang G, Yu H, Kirschner MW. Control of mitotic transitions by the anaphase-promoting complex. Philos Trans R Soc Lond B Biol Sci 1999;354:1583-90.
20. Baker DJ, Dawlaty MM, Galardy P, van Deursen JM. Mitotic regulation of the anaphase-promoting complex. Cell Mol Life Sci 2007;64:589-600.
21. Jang YJ, Ji JH, Choi YC, Ryu CJ, Ko SY. Regulation of Polo-like kinase 1 by DNA damage in mitosis. Inhibition of mitotic PLK-1 by protein phosphatase 2A. J Biol Chem 2007;282:2473-82.
22. Kondo J, Sato F, Kusumi T, Liu Y, Motonari O, Sato T, Kijima H. Claudin-1 expression is induced by tumor necrosis factor-alpha in human pancreatic cancer cells. Int J Mol Med 2008;22:645-9.
23. Hesry V, Piquet-Pellorce C, Travert M, Donaghy L, Jegou B, Patard JJ, Guillaudeux T. Sensitivity of prostate cells to TRAIL-induced apoptosis increases with tumor progression: DR5 and Caspase 8 are key players. Prostate 2006;66:987-95.
24. Mori T, Doi R, Toyoda E, Koizumi M, Ito D, Kami K, Kida A, Masui T, Kawaguchi Y, Fujimoto K. Regulation of the resistance to TRAIL-induced apoptosis as a new strategy for pancreatic cancer. Surgery 2005;138:71-7.
25. Efferth T, Rauh R, Kahl S, Tomicic M, Bochzelt H, Tome ME, Briehl MM, Bauer R, Kaina B. Molecular modes of action of Cantharidin in tumor cells. Biochem Pharmacol 2005;69:811-8.
26. Rauh R, Kahl S, Boechzelt H, Bauer R, Kaina B, Efferth T. Molecular biology of Cantharidin in cancer cells. Chin Med 2007;2:8.
27. Ozben T. Oxidative stress and apoptosis: impact on cancer therapy. J Pharm Sci 2007;96:2181-96.
28. Simon HU, Haj-Yehia A, Levi-Schaffer F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 2000;5:415-8.
29. Moore PS, Sipos B, Orlandini S, Sorio C, Real FX, Lemoine NR, Gress T, Bassi C, Kloppel G, Kalthoff H, Ungefroren H, Lohr M, et al. Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4. Virchows Arch 2001;439:798-802.
30. Hong CY, Huang SC, Lin SK, Lee JJ, Chueh LL, Lee CH, Lin JH, Hsiao M. NorCantharidin-induced post-G(2)/M apoptosis is dependent on wild-type p53 gene. Biochem Biophys Res Commun 2000;276:278-85.
31. Farrell JJ, van Rijnsoever M, Elsaleh H. Early detection markers in Pancreas Cancer. Cancer Biomark 2005;1:157-75.
32. Sela BA. Matrix metalloproteinases: promoters of tumor progression and invasiveness. Isr Med Assoc J 2002;4:280-2.
.1. Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001;358:1576-85.
2. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet 2004;363:1049-57.
3. Guo X, Cui Z. Current diagnosis and treatment of pancreatic cancer in China. Pancreas 2005;31:13-22.
4. Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 1999;24:186-91.
5. Chen LF, Greene WC. Shaping the nuclear action of NF-kappaB. Nat Rev Mol Cell Biol 2004;5:392-401.
6. Inoue J, Gohda J, Akiyama T, Semba K. NF-kappaB activation in development and progression of cancer. Cancer Sci 2007;98:268-74.
7. Gilmore T, Gapuzan ME, Kalaitzidis D, Starczynowski D. Rel/NF-kappa B/I kappa B signal transduction in the generation and treatment of human cancer. Cancer Lett 2002;181:1-9.
8. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 1997;388:548-54.
9. Danovi SA, Wong HH, Lemoine NR. Targeted therapies for pancreatic cancer. Br Med Bull 2008;87:97-130.
10. Dutta J, Fan Y, Gupta N, Fan G, Gelinas C. Current insights into the regulation of programmed cell death by NF-kappaB. Oncogene 2006;25:6800-16.
11. Radhakrishnan SK, Kamalakaran S. Pro-apoptotic role of NF-kappaB:implications for cancer therapy. Biochim Biophys Acta 2006;1766:53-62.
12. Campbell KJ, Rocha S, Perkins ND. Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B. Mol Cell 2004;13:853-65.
13. Miskolci V, Castro-Alcaraz S, Nguyen P, Vancura A, Davidson D, Vancurova I. Okadaic acid induces sustained activation of NFkappaB and degradation of the nuclear IkappaBalpha in human neutrophils. Arch Biochem Biophys 2003;417:44-52.
14. Shishodia S, Aggarwal BB. Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. J Biol Chem 2004;279:47148-58.
15. Chatfield K, Eastman A. Inhibitors of protein phosphatases 1 and 2A differentially prevent intrinsic and extrinsic apoptosis pathways. Biochem Biophys Res Commun 2004;323:1313-20.
16. McVicar DW, Mason AT, Bere EW, Ortaldo JR. Activation of peripheral large granular lymphocytes with the serine/threonine phosphatase inhibitor, okadaic acid. Eur J Immunol 1994;24:165-70.
17. Garcia I, Pipaon C, Alemany S, Perez-Castillo A. Induction of NGFI-B gene expression during T cell activation. Role of protein phosphatases. J Immunol 1994;153:3417-25.
18. Wang GS. Medical uses of mylabris in ancient China and recent studies. J Ethnopharmacol 1989;26:147-62.
19. Illi B, Dello Russo C, Colussi C, Rosati J, Pallaoro M, Spallotta F, Rotili D, Valente S, Ragone G, Martelli F, Biglioli P, Steinkuhler C, et al. Nitric oxide modulates chromatin folding in human endothelial cells via protein phosphatase 2A activation and class II histone deacetylases nuclear shuttling. Circ Res 2008;102:51-8.
.1. Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 1999;24:186-91.
2. Hemmings BA, Adams-Pearson C, Maurer F, Muller P, Goris J, Merlevede W, Hofsteenge J, Stone SR. alpha- and beta-forms of the 65-kDa subunit of protein phosphatase 2A have a similar 39 amino acid repeating structure. Biochemistry 1990;29:3166-73.
3. Zhou J, Pham HT, Ruediger R, Walter G. Characterization of the Aalpha and Abeta subunit isoforms of protein phosphatase 2A: differences in expression, subunit interaction, and evolution. Biochem J 2003;369:387-98.
4. Arino J, Woon CW, Brautigan DL, Miller TB, Jr., Johnson GL. Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic subunit isotypes. Proc Natl Acad Sci U S A 1988;85:4252-6.
5. Cohen P. The structure and regulation of protein phosphatases. Annu Rev Biochem 1989;58:453-508.
6. Mayer RE, Hendrix P, Cron P, Matthies R, Stone SR, Goris J, Merlevede W, Hofsteenge J, Hemmings BA. Structure of the 55-kDa regulatory subunit of protein phosphatase 2A: evidence for a neuronal-specific isoform. Biochemistry 1991;30:3589-97.
7. Strack S, Chang D, Zaucha JA, Colbran RJ, Wadzinski BE. Cloning and characterization of B delta, a novel regulatory subunit of protein phosphatase 2A. FEBS Lett 1999;460:462-6.
8. Zolnierowicz S, Csortos C, Bondor J, Verin A, Mumby MC, DePaoli-Roach AA. Diversity in the regulatory B-subunits of protein phosphatase 2A: identification of a novel isoform highly expressed in brain. Biochemistry 1994;33:11858-67.
9. Li X, Virshup DM. Two conserved domains in regulatory B subunits mediatebinding to the A subunit of protein phosphatase 2A. Eur J Biochem 2002;269:546-52.
10. Csortos C, Zolnierowicz S, Bako E, Durbin SD, DePaoli-Roach AA. High complexity in the expression of the B' subunit of protein phosphatase 2A0. Evidence for the existence of at least seven novel isoforms. J Biol Chem 1996;271:2578-88.
11. McCright B, Virshup DM. Identification of a new family of protein phosphatase 2A regulatory subunits. J Biol Chem 1995;270:26123-8.
12. Tehrani MA, Mumby MC, Kamibayashi C. Identification of a novel protein phosphatase 2A regulatory subunit highly expressed in muscle. J Biol Chem 1996;271:5164-70.
13. Hendrix P, Mayer-Jackel RE, Cron P, Goris J, Hofsteenge J, Merlevede W, Hemmings BA. Structure and expression of a 72-kDa regulatory subunit of protein phosphatase 2A. Evidence for different size forms produced by alternative splicing. J Biol Chem 1993;268:15267-76.
14. Stevens I, Janssens V, Martens E, Dilworth S, Goris J, Van Hoof C. Identification and characterization of B"-subunits of protein phosphatase 2 A in Xenopus laevis oocytes and adult tissues. Eur J Biochem 2003;270:376-87.
15. Voorhoeve PM, Agami R. The tumor-suppressive functions of the human INK4A locus. Cancer Cell 2003;4:311-9.
16. Yan Z, Fedorov SA, Mumby MC, Williams RS. PR48, a novel regulatory subunit of protein phosphatase 2A, interacts with Cdc6 and modulates DNA replication in human cells. Mol Cell Biol 2000;20:1021-9.
17. Moreno CS, Park S, Nelson K, Ashby D, Hubalek F, Lane WS, Pallas DC. WD40 repeat proteins striatin and S/G(2) nuclear autoantigen are members of a novel family of calmodulin-binding proteins that associate with protein phosphatase 2A. J Biol Chem 2000;275:5257-63.
18. Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, Yu JW, Strack S, Jeffrey PD,Shi Y. Structure of the protein phosphatase 2A holoenzyme. Cell 2006;127:1239-51.
19. Cho US, Xu W. Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 2007;445:53-7.
20. Chen W, Arroyo JD, Timmons JC, Possemato R, Hahn WC. Cancer-associated PP2A Aalpha subunits induce functional haploinsufficiency and tumorigenicity. Cancer Res 2005;65:8183-92.
21. Ruediger R, Pham HT, Walter G. Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the A beta subunit gene. Oncogene 2001;20:1892-9.
22. Ruediger R, Pham HT, Walter G. Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the A alpha subunit gene. Oncogene 2001;20:10-5.
23. Sablina AA, Chen W, Arroyo JD, Corral L, Hector M, Bulmer SE, DeCaprio JA, Hahn WC. The tumor suppressor PP2A Abeta regulates the RalA GTPase. Cell 2007;129:969-82.
24. Ruediger R, Fields K, Walter G. Binding specificity of protein phosphatase
2A core enzyme for regulatory B subunits and T antigens. J Virol 1999;73:839-42.
25. Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 2001;353:417-39.
26. Janssens V, Longin S, Goris J. PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci 2008;33:113-21.
27. Murata K, Wu J, Brautigan DL. 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 1997;94:10624-9.
28. Kong M, Fox CJ, Mu J, Solt L, Xu A, Cinalli RM, Birnbaum MJ, Lindsten T,Thompson CB. The PP2A-associated protein alpha4 is an essential inhibitor of apoptosis. Science 2004;306:695-8.
29. Rundell K, Parakati R. The role of the SV40 ST antigen in cell growth promotion and transformation. Semin Cancer Biol 2001;11:5-13.
30. Sullivan CS, Pipas JM. T antigens of simian virus 40: molecular chaperones for viral replication and tumorigenesis. Microbiol Mol Biol Rev 2002;66:179-202.
31. Drayton S, Rowe J, Jones R, Vatcheva R, Cuthbert-Heavens D, Marshall J, Fried M, Peters G. Tumor suppressor p16INK4a determines sensitivity of human cells to transformation by cooperating cellular oncogenes. Cancer Cell 2003;4:301-10.
32. Boehm JS, Hession MT, Bulmer SE, Hahn WC. Transformation of human and murine fibroblasts without viral oncoproteins. Mol Cell Biol 2005;25:6464-74.
33. Neviani P, Santhanam R, Oaks JJ, Eiring AM, Notari M, Blaser BW, Liu S, Trotta R, Muthusamy N, Gambacorti-Passerini C, Druker BJ, Cortes J, et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest 2007;117:2408-21.
34. Cho US, Morrone S, Sablina AA, Arroyo JD, Hahn WC, Xu W. Structural basis of PP2A inhibition by small t antigen. PLoS Biol 2007;5:e202.
35. Pallas DC, Shahrik LK, Martin BL, Jaspers S, Miller TB, Brautigan DL, Roberts TM. Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell 1990;60:167-76.
36. Walter G, Ruediger R, Slaughter C, Mumby M. Association of protein phosphatase 2A with polyoma virus medium tumor antigen. Proc Natl Acad Sci U S A 1990;87:2521-5.
37. Shtrichman R, Sharf R, Barr H, Dobner T, Kleinberger T. Induction of apoptosis by adenovirus E4orf4 protein is specific to transformed cells and requiresan interaction with protein phosphatase 2A. Proc Natl Acad Sci U S A 1999;96:10080-5.
38. Michalovitz D, Fischer-Fantuzzi L, Vesco C, Pipas JM, Oren M. Activated Ha-ras can cooperate with defective simian virus 40 in the transformation of nonestablished rat embryo fibroblasts. J Virol 1987;61:2648-54.
39. Hirakawa T, Ruley HE. Rescue of cells from ras oncogene-induced growth arrest by a second, complementing, oncogene. Proc Natl Acad Sci U S A 1988;85:1519-23.
40. Sager R, Tanaka K, Lau CC, Ebina Y, Anisowicz A. Resistance of human cells to tumorigenesis induced by cloned transforming genes. Proc Natl Acad Sci U S A 1983;80:7601-5.
41. Chang LS, Pan S, Pater MM, Di Mayorca G. Differential requirement for SV40 early genes in immortalization and transformation of primary rat and human embryonic cells. Virology 1985;146:246-61.
42. Lustig AJ. Crisis intervention: the role of telomerase. Proc Natl Acad Sci U S A 1999;96:3339-41.
43. Hahn WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM, DeCaprio JA, Weinberg RA. Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol Cell Biol 2002;22:2111-23.
44. Rangarajan A, Hong SJ, Gifford A, Weinberg RA. Species- and cell type-specific requirements for cellular transformation. Cancer Cell 2004;6:171-83.
45. Yu J, Boyapati A, Rundell K. Critical role for SV40 small-t antigen in human cell transformation. Virology 2001;290:192-8.
46. Mungre S, Enderle K, Turk B, Porras A, Wu YQ, Mumby MC, Rundell K. Mutations which affect the inhibition of protein phosphatase 2A by simian virus 40 small-t antigen in vitro decrease viral transformation. J Virol 1994;68:1675-81.
47. Porras A, Bennett J, Howe A, Tokos K, Bouck N, Henglein B, Sathyamangalam S, Thimmapaya B, Rundell K. A novel simian virus 40 early-region domain mediates transactivation of the cyclin A promoter by small-t antigen and is required for transformation in small-t antigen-dependent assays. J Virol 1996;70:6902-8.
48. Chen W, Possemato R, Campbell KT, Plattner CA, Pallas DC, Hahn WC. Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell 2004;5:127-36.
49. Francia G, Mitchell SD, Moss SE, Hanby AM, Marshall JF, Hart IR. Identification by differential display of annexin-VI, a gene differentially expressed during melanoma progression. Cancer Res 1996;56:3855-8.
50. Deichmann M, Polychronidis M, Wacker J, Thome M, Naher H. The protein phosphatase 2A subunit Bgamma gene is identified to be differentially expressed in malignant melanomas by subtractive suppression hybridization. Melanoma Res 2001;11:577-85.
51. Calin GA, di Iasio MG, Caprini E, Vorechovsky I, Natali PG, Sozzi G, Croce CM, Barbanti-Brodano G, Russo G, Negrini M. 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 2000;19:1191-5.
52. Takagi Y, Futamura M, Yamaguchi K, Aoki S, Takahashi T, Saji S. Alterations of the PPP2R1B gene located at 11q23 in human colorectal cancers. Gut 2000;47:268-71.
53. Tamaki M, Goi T, Hirono Y, Katayama K, Yamaguchi A. PPP2R1B gene alterations inhibit interaction of PP2A-Abeta and PP2A-C proteins in colorectal cancers. Oncol Rep 2004;11:655-9.
54. Wang SS, Esplin ED, Li JL, Huang L, Gazdar A, Minna J, Evans GA.Alterations of the PPP2R1B gene in human lung and colon cancer. Science 1998;282:284-7.
55. Li X, Scuderi A, Letsou A, Virshup DM. B56-associated protein phosphatase
2A is required for survival and protects from apoptosis in Drosophila melanogaster. Mol Cell Biol 2002;22:3674-84.
56. Strack S, Cribbs JT, Gomez L. Critical role for protein phosphatase 2A heterotrimers in mammalian cell survival. J Biol Chem 2004;279:47732-9.
57. Silverstein AM, Barrow CA, Davis AJ, Mumby MC. Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits. Proc Natl Acad Sci U S A 2002;99:4221-6.
58. Yuan H, Veldman T, Rundell K, Schlegel R. Simian virus 40 small tumor antigen activates AKT and telomerase and induces anchorage-independent growth of human epithelial cells. J Virol 2002;76:10685-91.
59. Zhao JJ, Gjoerup OV, Subramanian RR, Cheng Y, Chen W, Roberts TM, Hahn WC. Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3-kinase. Cancer Cell 2003;3:483-95.
60. Polakis P. Wnt signaling and cancer. Genes Dev 2000;14:1837-51.
61. Creyghton MP, Roel G, Eichhorn PJ, Hijmans EM, Maurer I, Destree O, Bernards R. PR72, a novel regulator of Wnt signaling required for Naked cuticle function. Genes Dev 2005;19:376-86.
62. Creyghton MP, Roel G, Eichhorn PJ, Vredeveld LC, Destree O, Bernards R. PR130 is a modulator of the Wnt-signaling cascade that counters repression of the antagonist Naked cuticle. Proc Natl Acad Sci U S A 2006;103:5397-402.
63. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000;103:311-20.
64. Li HH, Cai X, Shouse GP, Piluso LG, Liu X. A specific PP2A regulatorysubunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55. EMBO J 2007;26:402-11.
65. Okamoto K, Li H, Jensen MR, Zhang T, Taya Y, Thorgeirsson SS, Prives C. Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol Cell 2002;9:761-71.
66. Wei W, Jobling WA, Chen W, Hahn WC, Sedivy JM. Abolition of cyclin-dependent kinase inhibitor p16Ink4a and p21Cip1/Waf1 functions permits Ras-induced anchorage-independent growth in telomerase-immortalized human fibroblasts. Mol Cell Biol 2003;23:2859-70.
67. Feig LA. Ral-GTPases: approaching their 15 minutes of fame. Trends Cell Biol 2003;13:419-25.
68. Chien Y, Kim S, Bumeister R, Loo YM, Kwon SW, Johnson CL, Balakireva MG, Romeo Y, Kopelovich L, Gale M, Jr., Yeaman C, Camonis JH, et al. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 2006;127:157-70.
69. Chien Y, White MA. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO Rep 2003;4:800-6.
70. Lim KH, Baines AT, Fiordalisi JJ, Shipitsin M, Feig LA, Cox AD, Der CJ, Counter CM. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 2005;7:533-45.
71. Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, Sjostrom SK, Garraway LA, Weremowicz S, Richardson AL, Greulich H, Stewart CJ, et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 2007;129:1065-79.
72. Hamad NM, Elconin JH, Karnoub AE, Bai W, Rich JN, Abraham RT, Der CJ, Counter CM. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev 2002;16:2045-57.
73. Camonis JH, White MA. Ral GTPases: corrupting the exocyst in cancer cells. Trends Cell Biol 2005;15:327-32.
74. Feinstein E. Ral-GTPases: good chances for a long-lasting fame. Oncogene 2005;24:326-8.
75. Goi T, Shipitsin M, Lu Z, Foster DA, Klinz SG, Feig LA. An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity. EMBO J 2000;19:623-30.
76. Jiang H, Luo JQ, Urano T, Frankel P, Lu Z, Foster DA, Feig LA. Involvement of Ral GTPase in v-Src-induced phospholipase D activation. Nature 1995;378:409-12.
77. Moskalenko S, Henry DO, Rosse C, Mirey G, Camonis JH, White MA. The exocyst is a Ral effector complex. Nat Cell Biol 2002;4:66-72.
78. Adler HT, Nallaseth FS, Walter G, Tkachuk DC. HRX leukemic fusion proteins form a heterocomplex with the leukemia-associated protein SET and protein phosphatase 2A. J Biol Chem 1997;272:28407-14.
79. Gildea JJ, Harding MA, Seraj MJ, Gulding KM, Theodorescu D. The role of Ral A in epidermal growth factor receptor-regulated cell motility. Cancer Res 2002;62:982-5.
80. Ohta Y, Suzuki N, Nakamura S, Hartwig JH, Stossel TP. The small GTPase RalA targets filamin to induce filopodia. Proc Natl Acad Sci U S A 1999;96:2122-8.
81. Tchevkina E, Agapova L, Dyakova N, Martinjuk A, Komelkov A, Tatosyan A. The small G-protein RalA stimulates metastasis of transformed cells. Oncogene 2005;24:329-35.
82. Panner A, Nakamura JL, Parsa AT, Rodriguez-Viciana P, Berger MS, Stokoe D, Pieper RO. mTOR-independent translational control of the extrinsic cell death pathway by RalA. Mol Cell Biol 2006;26:7345-57.
83. Katoh F, Fitzgerald DJ, Giroldi L, Fujiki H, Sugimura T, Yamasaki H. Okadaic acid and phorbol esters: comparative effects of these tumor promoters on cell transformation, intercellular communication and differentiation in vitro. Jpn J Cancer Res 1990;81:590-7.
84. Sontag E, Fedorov S, Kamibayashi C, Robbins D, Cobb M, Mumby M. The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation. Cell 1993;75:887-97.
85. Li M, Guo H, Damuni Z. Purification and characterization of two potent heat-stable protein inhibitors of protein phosphatase 2A from bovine kidney. Biochemistry 1995;34:1988-96.
86. Katayose Y, Li M, Al-Murrani SW, Shenolikar S, Damuni Z. Protein phosphatase 2A inhibitors, I(1)(PP2A) and I(2)(PP2A), associate with and modify the substrate specificity of protein phosphatase 1. J Biol Chem 2000;275:9209-14.
87. Andersson A, Ritz C, Lindgren D, Eden P, Lassen C, Heldrup J, Olofsson T, Rade J, Fontes M, Porwit-Macdonald A, Behrendtz M, Hoglund M, et al. Microarray-based classification of a consecutive series of 121 childhood acute leukemias: prediction of leukemic and genetic subtype as well as of minimal residual disease status. Leukemia 2007;21:1198-203.
88. Ginos MA, Page GP, Michalowicz BS, Patel KJ, Volker SE, Pambuccian SE, Ondrey FG, Adams GL, Gaffney PM. Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck. Cancer Res 2004;64:55-63.
89. Korkola JE, Houldsworth J, Chadalavada RS, Olshen AB, Dobrzynski D, Reuter VE, Bosl GJ, Chaganti RS. Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors. Cancer Res 2006;66:820-7.
90. Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S, Passaniti A, Menon J, Walling J, Bailey R, Rosenblum M, Mikkelsen T, et al. Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell 2006;9:287-300.
91. Carlson SG, Eng E, Kim EG, Perlman EJ, Copeland TD, Ballermann BJ. Expression of SET, an inhibitor of protein phosphatase 2A, in renal development and Wilms' tumor. J Am Soc Nephrol 1998;9:1873-80.
92. Junttila MR, Li SP, Westermarck J. Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J 2008;22:954-65.
93. Westermarck J, Holmstrom T, Ahonen M, Eriksson JE, Kahari VM. Enhancement of fibroblast collagenase-1 (MMP-1) gene expression by tumor promoter okadaic acid is mediated by stress-activated protein kinases Jun N-terminal kinase and p38. Matrix Biol 1998;17:547-57.
94. Al-Murrani SW, Woodgett JR, Damuni Z. Expression of I2PP2A, an inhibitor of protein phosphatase 2A, induces c-Jun and AP-1 activity. Biochem J 1999;341 ( Pt 2):293-8.
95. Harmala-Brasken AS, Mikhailov A, Soderstrom TS, Meinander A, Holmstrom TH, Damuni Z, Eriksson JE. Type-2A protein phosphatase activity is required to maintain death receptor responsiveness. Oncogene 2003;22:7677-86.
96. Li M, Makkinje A, Damuni Z. The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. J Biol Chem 1996;271:11059-62.
97. Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S, Mao H, Chang JS, Galietta A, Uttam A, Roy DC, Valtieri M, et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell 2005;8:355-68.
98. Adhikary S, Eilers M. Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 2005;6:635-45.
99. Blancato J, Singh B, Liu A, Liao DJ, Dickson RB. Correlation of amplification and overexpression of the c-myc oncogene in high-grade breast cancer: FISH, in situ hybridisation and immunohistochemical analyses. Br J Cancer 2004;90:1612-9.
100. Liao DJ, Dickson RB. c-Myc in breast cancer. Endocr Relat Cancer 2000;7:143-64.
101. Gregory MA, Hann SR. c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt's lymphoma cells. Mol Cell Biol 2000;20:2423-35.
102. Malempati S, Tibbitts D, Cunningham M, Akkari Y, Olson S, Fan G, Sears RC. Aberrant stabilization of c-Myc protein in some lymphoblastic leukemias. Leukemia 2006;20:1572-81.
103. Vervoorts J, Luscher-Firzlaff J, Luscher B. The ins and outs of MYC regulation by posttranslational mechanisms. J Biol Chem 2006;281:34725-9.
104. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 2000;14:2501-14.
105. Sears R, Leone G, DeGregori J, Nevins JR. Ras enhances Myc protein stability. Mol Cell 1999;3:169-79.
106. Arnold HK, Sears RC. Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation. Mol Cell Biol 2006;26:2832-44.
107. Sears RC. The life cycle of C-myc: from synthesis to degradation. Cell Cycle 2004;3:1133-7.
108. Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G, Hahn WC, Stukenberg PT, Shenolikar S, Uchida T, Counter CM, Nevins JR, et al. A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol 2004;6:308-18.
109. Junttila MR, Puustinen P, Niemela M, Ahola R, Arnold H, Bottzauw T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, Lu SL, Lin S, et al. CIP2A inhibits PP2A in human malignancies. Cell 2007;130:51-62.
110. Soo Hoo L, Zhang JY, Chan EK. Cloning and characterization of a novel 90 kDa 'companion' auto-antigen of p62 overexpressed in cancer. Oncogene 2002;21:5006-15.
111. Longin S, Jordens J, Martens E, Stevens I, Janssens V, Rondelez E, De Baere I, Derua R, Waelkens E, Goris J, Van Hoof C. An inactive protein phosphatase
2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator. Biochem J 2004;380:111-9.
112. Ogris E, Du X, Nelson KC, Mak EK, Yu XX, Lane WS, Pallas DC. A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2A. J Biol Chem 1999;274:14382-91.
113. McConnell JL, Gomez RJ, McCorvey LR, Law BK, Wadzinski BE. Identification of a PP2A-interacting protein that functions as a negative regulator of phosphatase activity in the ATM/ATR signaling pathway. Oncogene 2007;26:6021-30.
2. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet 2004;363:1049-57.
3. Guo X, Cui Z. Current diagnosis and treatment of pancreatic cancer in China. Pancreas 2005;31:13-22.
4. Danovi SA, Wong HH, Lemoine NR. Targeted therapies for pancreatic cancer. Br Med Bull 2008;87:97-130.
5. Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer 2002;2:897-909.
6. Wang GS. Medical uses of mylabris in ancient China and recent studies. J Ethnopharmacol 1989;26:147-62.
7. Honkanen RE. Cantharidin, another natural toxin that inhibits the activity of serine/threonine protein phosphatases types 1 and 2A. FEBS Lett 1993;330:283-6.
8. Huh JE, Kang KS, Chae C, Kim HM, Ahn KS, Kim SH. Roles of p38 and JNK mitogen-activated protein kinase pathways during Cantharidin-induced apoptosis in U937 cells. Biochem Pharmacol 2004;67:1811-8.
9. Chen YN, Chen JC, Yin SC, Wang GS, Tsauer W, Hsu SF, Hsu SL. Effector mechanisms of norCantharidin-induced mitotic arrest and apoptosis in human hepatoma cells. Int J Cancer 2002;100:158-65.
10. Fan YZ, Fu JY, Zhao ZM, Chen CQ. Inhibitory effect of norCantharidin on the growth of human gallbladder carcinoma GBC-SD cells in vitro. Hepatobiliary Pancreat Dis Int 2007;6:72-80.
11. Peng F, Wei YQ, Tian L, Yang L, Zhao X, Lu Y, Mao YQ, Kan B, Lei S, Wang GS, Jiang Y, Wang QR, et al. Induction of apoptosis by norCantharidin in human colorectal carcinoma cell lines: involvement of the CD95 receptor/ligand. J Cancer Res Clin Oncol 2002;128:223-30.
12. Huan SK, Lee HH, Liu DZ, Wu CC, Wang CC. Cantharidin-induced cytotoxicity and cyclooxygenase 2 expression in human bladder carcinoma cell line. Toxicology 2006;223:136-43.
13. Schafer KA. The cell cycle: a review. Vet Pathol 1998;35:461-78.
14. van den Heuvel S. Cell-cycle regulation. WormBook 2005:1-16.
15. Riedl SJ, Shi Y. Molecular mechanisms of Caspase regulation during apoptosis. Nat Rev Mol Cell Biol 2004;5:897-907.
16. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008;9:47-59.
17. Joyce D, Albanese C, Steer J, Fu M, Bouzahzah B, Pestell RG. NF-kappaB and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev 2001;12:73-90.
18. Stark GR, Taylor WR. Control of the G2/M transition. Mol Biotechnol 2006;32:227-48.
19. Fang G, Yu H, Kirschner MW. Control of mitotic transitions by the anaphase-promoting complex. Philos Trans R Soc Lond B Biol Sci 1999;354:1583-90.
20. Baker DJ, Dawlaty MM, Galardy P, van Deursen JM. Mitotic regulation of the anaphase-promoting complex. Cell Mol Life Sci 2007;64:589-600.
21. Jang YJ, Ji JH, Choi YC, Ryu CJ, Ko SY. Regulation of Polo-like kinase 1 by DNA damage in mitosis. Inhibition of mitotic PLK-1 by protein phosphatase 2A. J Biol Chem 2007;282:2473-82.
22. Kondo J, Sato F, Kusumi T, Liu Y, Motonari O, Sato T, Kijima H. Claudin-1 expression is induced by tumor necrosis factor-alpha in human pancreatic cancer cells. Int J Mol Med 2008;22:645-9.
23. Hesry V, Piquet-Pellorce C, Travert M, Donaghy L, Jegou B, Patard JJ, Guillaudeux T. Sensitivity of prostate cells to TRAIL-induced apoptosis increases with tumor progression: DR5 and Caspase 8 are key players. Prostate 2006;66:987-95.
24. Mori T, Doi R, Toyoda E, Koizumi M, Ito D, Kami K, Kida A, Masui T, Kawaguchi Y, Fujimoto K. Regulation of the resistance to TRAIL-induced apoptosis as a new strategy for pancreatic cancer. Surgery 2005;138:71-7.
25. Efferth T, Rauh R, Kahl S, Tomicic M, Bochzelt H, Tome ME, Briehl MM, Bauer R, Kaina B. Molecular modes of action of Cantharidin in tumor cells. Biochem Pharmacol 2005;69:811-8.
26. Rauh R, Kahl S, Boechzelt H, Bauer R, Kaina B, Efferth T. Molecular biology of Cantharidin in cancer cells. Chin Med 2007;2:8.
27. Ozben T. Oxidative stress and apoptosis: impact on cancer therapy. J Pharm Sci 2007;96:2181-96.
28. Simon HU, Haj-Yehia A, Levi-Schaffer F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 2000;5:415-8.
29. Moore PS, Sipos B, Orlandini S, Sorio C, Real FX, Lemoine NR, Gress T, Bassi C, Kloppel G, Kalthoff H, Ungefroren H, Lohr M, et al. Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4. Virchows Arch 2001;439:798-802.
30. Hong CY, Huang SC, Lin SK, Lee JJ, Chueh LL, Lee CH, Lin JH, Hsiao M. NorCantharidin-induced post-G(2)/M apoptosis is dependent on wild-type p53 gene. Biochem Biophys Res Commun 2000;276:278-85.
31. Farrell JJ, van Rijnsoever M, Elsaleh H. Early detection markers in Pancreas Cancer. Cancer Biomark 2005;1:157-75.
32. Sela BA. Matrix metalloproteinases: promoters of tumor progression and invasiveness. Isr Med Assoc J 2002;4:280-2.
.1. Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001;358:1576-85.
2. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet 2004;363:1049-57.
3. Guo X, Cui Z. Current diagnosis and treatment of pancreatic cancer in China. Pancreas 2005;31:13-22.
4. Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 1999;24:186-91.
5. Chen LF, Greene WC. Shaping the nuclear action of NF-kappaB. Nat Rev Mol Cell Biol 2004;5:392-401.
6. Inoue J, Gohda J, Akiyama T, Semba K. NF-kappaB activation in development and progression of cancer. Cancer Sci 2007;98:268-74.
7. Gilmore T, Gapuzan ME, Kalaitzidis D, Starczynowski D. Rel/NF-kappa B/I kappa B signal transduction in the generation and treatment of human cancer. Cancer Lett 2002;181:1-9.
8. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 1997;388:548-54.
9. Danovi SA, Wong HH, Lemoine NR. Targeted therapies for pancreatic cancer. Br Med Bull 2008;87:97-130.
10. Dutta J, Fan Y, Gupta N, Fan G, Gelinas C. Current insights into the regulation of programmed cell death by NF-kappaB. Oncogene 2006;25:6800-16.
11. Radhakrishnan SK, Kamalakaran S. Pro-apoptotic role of NF-kappaB:implications for cancer therapy. Biochim Biophys Acta 2006;1766:53-62.
12. Campbell KJ, Rocha S, Perkins ND. Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B. Mol Cell 2004;13:853-65.
13. Miskolci V, Castro-Alcaraz S, Nguyen P, Vancura A, Davidson D, Vancurova I. Okadaic acid induces sustained activation of NFkappaB and degradation of the nuclear IkappaBalpha in human neutrophils. Arch Biochem Biophys 2003;417:44-52.
14. Shishodia S, Aggarwal BB. Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. J Biol Chem 2004;279:47148-58.
15. Chatfield K, Eastman A. Inhibitors of protein phosphatases 1 and 2A differentially prevent intrinsic and extrinsic apoptosis pathways. Biochem Biophys Res Commun 2004;323:1313-20.
16. McVicar DW, Mason AT, Bere EW, Ortaldo JR. Activation of peripheral large granular lymphocytes with the serine/threonine phosphatase inhibitor, okadaic acid. Eur J Immunol 1994;24:165-70.
17. Garcia I, Pipaon C, Alemany S, Perez-Castillo A. Induction of NGFI-B gene expression during T cell activation. Role of protein phosphatases. J Immunol 1994;153:3417-25.
18. Wang GS. Medical uses of mylabris in ancient China and recent studies. J Ethnopharmacol 1989;26:147-62.
19. Illi B, Dello Russo C, Colussi C, Rosati J, Pallaoro M, Spallotta F, Rotili D, Valente S, Ragone G, Martelli F, Biglioli P, Steinkuhler C, et al. Nitric oxide modulates chromatin folding in human endothelial cells via protein phosphatase 2A activation and class II histone deacetylases nuclear shuttling. Circ Res 2008;102:51-8.
.1. Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 1999;24:186-91.
2. Hemmings BA, Adams-Pearson C, Maurer F, Muller P, Goris J, Merlevede W, Hofsteenge J, Stone SR. alpha- and beta-forms of the 65-kDa subunit of protein phosphatase 2A have a similar 39 amino acid repeating structure. Biochemistry 1990;29:3166-73.
3. Zhou J, Pham HT, Ruediger R, Walter G. Characterization of the Aalpha and Abeta subunit isoforms of protein phosphatase 2A: differences in expression, subunit interaction, and evolution. Biochem J 2003;369:387-98.
4. Arino J, Woon CW, Brautigan DL, Miller TB, Jr., Johnson GL. Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic subunit isotypes. Proc Natl Acad Sci U S A 1988;85:4252-6.
5. Cohen P. The structure and regulation of protein phosphatases. Annu Rev Biochem 1989;58:453-508.
6. Mayer RE, Hendrix P, Cron P, Matthies R, Stone SR, Goris J, Merlevede W, Hofsteenge J, Hemmings BA. Structure of the 55-kDa regulatory subunit of protein phosphatase 2A: evidence for a neuronal-specific isoform. Biochemistry 1991;30:3589-97.
7. Strack S, Chang D, Zaucha JA, Colbran RJ, Wadzinski BE. Cloning and characterization of B delta, a novel regulatory subunit of protein phosphatase 2A. FEBS Lett 1999;460:462-6.
8. Zolnierowicz S, Csortos C, Bondor J, Verin A, Mumby MC, DePaoli-Roach AA. Diversity in the regulatory B-subunits of protein phosphatase 2A: identification of a novel isoform highly expressed in brain. Biochemistry 1994;33:11858-67.
9. Li X, Virshup DM. Two conserved domains in regulatory B subunits mediatebinding to the A subunit of protein phosphatase 2A. Eur J Biochem 2002;269:546-52.
10. Csortos C, Zolnierowicz S, Bako E, Durbin SD, DePaoli-Roach AA. High complexity in the expression of the B' subunit of protein phosphatase 2A0. Evidence for the existence of at least seven novel isoforms. J Biol Chem 1996;271:2578-88.
11. McCright B, Virshup DM. Identification of a new family of protein phosphatase 2A regulatory subunits. J Biol Chem 1995;270:26123-8.
12. Tehrani MA, Mumby MC, Kamibayashi C. Identification of a novel protein phosphatase 2A regulatory subunit highly expressed in muscle. J Biol Chem 1996;271:5164-70.
13. Hendrix P, Mayer-Jackel RE, Cron P, Goris J, Hofsteenge J, Merlevede W, Hemmings BA. Structure and expression of a 72-kDa regulatory subunit of protein phosphatase 2A. Evidence for different size forms produced by alternative splicing. J Biol Chem 1993;268:15267-76.
14. Stevens I, Janssens V, Martens E, Dilworth S, Goris J, Van Hoof C. Identification and characterization of B"-subunits of protein phosphatase 2 A in Xenopus laevis oocytes and adult tissues. Eur J Biochem 2003;270:376-87.
15. Voorhoeve PM, Agami R. The tumor-suppressive functions of the human INK4A locus. Cancer Cell 2003;4:311-9.
16. Yan Z, Fedorov SA, Mumby MC, Williams RS. PR48, a novel regulatory subunit of protein phosphatase 2A, interacts with Cdc6 and modulates DNA replication in human cells. Mol Cell Biol 2000;20:1021-9.
17. Moreno CS, Park S, Nelson K, Ashby D, Hubalek F, Lane WS, Pallas DC. WD40 repeat proteins striatin and S/G(2) nuclear autoantigen are members of a novel family of calmodulin-binding proteins that associate with protein phosphatase 2A. J Biol Chem 2000;275:5257-63.
18. Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, Yu JW, Strack S, Jeffrey PD,Shi Y. Structure of the protein phosphatase 2A holoenzyme. Cell 2006;127:1239-51.
19. Cho US, Xu W. Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 2007;445:53-7.
20. Chen W, Arroyo JD, Timmons JC, Possemato R, Hahn WC. Cancer-associated PP2A Aalpha subunits induce functional haploinsufficiency and tumorigenicity. Cancer Res 2005;65:8183-92.
21. Ruediger R, Pham HT, Walter G. Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the A beta subunit gene. Oncogene 2001;20:1892-9.
22. Ruediger R, Pham HT, Walter G. Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the A alpha subunit gene. Oncogene 2001;20:10-5.
23. Sablina AA, Chen W, Arroyo JD, Corral L, Hector M, Bulmer SE, DeCaprio JA, Hahn WC. The tumor suppressor PP2A Abeta regulates the RalA GTPase. Cell 2007;129:969-82.
24. Ruediger R, Fields K, Walter G. Binding specificity of protein phosphatase
2A core enzyme for regulatory B subunits and T antigens. J Virol 1999;73:839-42.
25. Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 2001;353:417-39.
26. Janssens V, Longin S, Goris J. PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci 2008;33:113-21.
27. Murata K, Wu J, Brautigan DL. 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 1997;94:10624-9.
28. Kong M, Fox CJ, Mu J, Solt L, Xu A, Cinalli RM, Birnbaum MJ, Lindsten T,Thompson CB. The PP2A-associated protein alpha4 is an essential inhibitor of apoptosis. Science 2004;306:695-8.
29. Rundell K, Parakati R. The role of the SV40 ST antigen in cell growth promotion and transformation. Semin Cancer Biol 2001;11:5-13.
30. Sullivan CS, Pipas JM. T antigens of simian virus 40: molecular chaperones for viral replication and tumorigenesis. Microbiol Mol Biol Rev 2002;66:179-202.
31. Drayton S, Rowe J, Jones R, Vatcheva R, Cuthbert-Heavens D, Marshall J, Fried M, Peters G. Tumor suppressor p16INK4a determines sensitivity of human cells to transformation by cooperating cellular oncogenes. Cancer Cell 2003;4:301-10.
32. Boehm JS, Hession MT, Bulmer SE, Hahn WC. Transformation of human and murine fibroblasts without viral oncoproteins. Mol Cell Biol 2005;25:6464-74.
33. Neviani P, Santhanam R, Oaks JJ, Eiring AM, Notari M, Blaser BW, Liu S, Trotta R, Muthusamy N, Gambacorti-Passerini C, Druker BJ, Cortes J, et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest 2007;117:2408-21.
34. Cho US, Morrone S, Sablina AA, Arroyo JD, Hahn WC, Xu W. Structural basis of PP2A inhibition by small t antigen. PLoS Biol 2007;5:e202.
35. Pallas DC, Shahrik LK, Martin BL, Jaspers S, Miller TB, Brautigan DL, Roberts TM. Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell 1990;60:167-76.
36. Walter G, Ruediger R, Slaughter C, Mumby M. Association of protein phosphatase 2A with polyoma virus medium tumor antigen. Proc Natl Acad Sci U S A 1990;87:2521-5.
37. Shtrichman R, Sharf R, Barr H, Dobner T, Kleinberger T. Induction of apoptosis by adenovirus E4orf4 protein is specific to transformed cells and requiresan interaction with protein phosphatase 2A. Proc Natl Acad Sci U S A 1999;96:10080-5.
38. Michalovitz D, Fischer-Fantuzzi L, Vesco C, Pipas JM, Oren M. Activated Ha-ras can cooperate with defective simian virus 40 in the transformation of nonestablished rat embryo fibroblasts. J Virol 1987;61:2648-54.
39. Hirakawa T, Ruley HE. Rescue of cells from ras oncogene-induced growth arrest by a second, complementing, oncogene. Proc Natl Acad Sci U S A 1988;85:1519-23.
40. Sager R, Tanaka K, Lau CC, Ebina Y, Anisowicz A. Resistance of human cells to tumorigenesis induced by cloned transforming genes. Proc Natl Acad Sci U S A 1983;80:7601-5.
41. Chang LS, Pan S, Pater MM, Di Mayorca G. Differential requirement for SV40 early genes in immortalization and transformation of primary rat and human embryonic cells. Virology 1985;146:246-61.
42. Lustig AJ. Crisis intervention: the role of telomerase. Proc Natl Acad Sci U S A 1999;96:3339-41.
43. Hahn WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM, DeCaprio JA, Weinberg RA. Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol Cell Biol 2002;22:2111-23.
44. Rangarajan A, Hong SJ, Gifford A, Weinberg RA. Species- and cell type-specific requirements for cellular transformation. Cancer Cell 2004;6:171-83.
45. Yu J, Boyapati A, Rundell K. Critical role for SV40 small-t antigen in human cell transformation. Virology 2001;290:192-8.
46. Mungre S, Enderle K, Turk B, Porras A, Wu YQ, Mumby MC, Rundell K. Mutations which affect the inhibition of protein phosphatase 2A by simian virus 40 small-t antigen in vitro decrease viral transformation. J Virol 1994;68:1675-81.
47. Porras A, Bennett J, Howe A, Tokos K, Bouck N, Henglein B, Sathyamangalam S, Thimmapaya B, Rundell K. A novel simian virus 40 early-region domain mediates transactivation of the cyclin A promoter by small-t antigen and is required for transformation in small-t antigen-dependent assays. J Virol 1996;70:6902-8.
48. Chen W, Possemato R, Campbell KT, Plattner CA, Pallas DC, Hahn WC. Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell 2004;5:127-36.
49. Francia G, Mitchell SD, Moss SE, Hanby AM, Marshall JF, Hart IR. Identification by differential display of annexin-VI, a gene differentially expressed during melanoma progression. Cancer Res 1996;56:3855-8.
50. Deichmann M, Polychronidis M, Wacker J, Thome M, Naher H. The protein phosphatase 2A subunit Bgamma gene is identified to be differentially expressed in malignant melanomas by subtractive suppression hybridization. Melanoma Res 2001;11:577-85.
51. Calin GA, di Iasio MG, Caprini E, Vorechovsky I, Natali PG, Sozzi G, Croce CM, Barbanti-Brodano G, Russo G, Negrini M. 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 2000;19:1191-5.
52. Takagi Y, Futamura M, Yamaguchi K, Aoki S, Takahashi T, Saji S. Alterations of the PPP2R1B gene located at 11q23 in human colorectal cancers. Gut 2000;47:268-71.
53. Tamaki M, Goi T, Hirono Y, Katayama K, Yamaguchi A. PPP2R1B gene alterations inhibit interaction of PP2A-Abeta and PP2A-C proteins in colorectal cancers. Oncol Rep 2004;11:655-9.
54. Wang SS, Esplin ED, Li JL, Huang L, Gazdar A, Minna J, Evans GA.Alterations of the PPP2R1B gene in human lung and colon cancer. Science 1998;282:284-7.
55. Li X, Scuderi A, Letsou A, Virshup DM. B56-associated protein phosphatase
2A is required for survival and protects from apoptosis in Drosophila melanogaster. Mol Cell Biol 2002;22:3674-84.
56. Strack S, Cribbs JT, Gomez L. Critical role for protein phosphatase 2A heterotrimers in mammalian cell survival. J Biol Chem 2004;279:47732-9.
57. Silverstein AM, Barrow CA, Davis AJ, Mumby MC. Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits. Proc Natl Acad Sci U S A 2002;99:4221-6.
58. Yuan H, Veldman T, Rundell K, Schlegel R. Simian virus 40 small tumor antigen activates AKT and telomerase and induces anchorage-independent growth of human epithelial cells. J Virol 2002;76:10685-91.
59. Zhao JJ, Gjoerup OV, Subramanian RR, Cheng Y, Chen W, Roberts TM, Hahn WC. Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3-kinase. Cancer Cell 2003;3:483-95.
60. Polakis P. Wnt signaling and cancer. Genes Dev 2000;14:1837-51.
61. Creyghton MP, Roel G, Eichhorn PJ, Hijmans EM, Maurer I, Destree O, Bernards R. PR72, a novel regulator of Wnt signaling required for Naked cuticle function. Genes Dev 2005;19:376-86.
62. Creyghton MP, Roel G, Eichhorn PJ, Vredeveld LC, Destree O, Bernards R. PR130 is a modulator of the Wnt-signaling cascade that counters repression of the antagonist Naked cuticle. Proc Natl Acad Sci U S A 2006;103:5397-402.
63. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000;103:311-20.
64. Li HH, Cai X, Shouse GP, Piluso LG, Liu X. A specific PP2A regulatorysubunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55. EMBO J 2007;26:402-11.
65. Okamoto K, Li H, Jensen MR, Zhang T, Taya Y, Thorgeirsson SS, Prives C. Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol Cell 2002;9:761-71.
66. Wei W, Jobling WA, Chen W, Hahn WC, Sedivy JM. Abolition of cyclin-dependent kinase inhibitor p16Ink4a and p21Cip1/Waf1 functions permits Ras-induced anchorage-independent growth in telomerase-immortalized human fibroblasts. Mol Cell Biol 2003;23:2859-70.
67. Feig LA. Ral-GTPases: approaching their 15 minutes of fame. Trends Cell Biol 2003;13:419-25.
68. Chien Y, Kim S, Bumeister R, Loo YM, Kwon SW, Johnson CL, Balakireva MG, Romeo Y, Kopelovich L, Gale M, Jr., Yeaman C, Camonis JH, et al. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 2006;127:157-70.
69. Chien Y, White MA. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO Rep 2003;4:800-6.
70. Lim KH, Baines AT, Fiordalisi JJ, Shipitsin M, Feig LA, Cox AD, Der CJ, Counter CM. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 2005;7:533-45.
71. Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, Sjostrom SK, Garraway LA, Weremowicz S, Richardson AL, Greulich H, Stewart CJ, et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 2007;129:1065-79.
72. Hamad NM, Elconin JH, Karnoub AE, Bai W, Rich JN, Abraham RT, Der CJ, Counter CM. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev 2002;16:2045-57.
73. Camonis JH, White MA. Ral GTPases: corrupting the exocyst in cancer cells. Trends Cell Biol 2005;15:327-32.
74. Feinstein E. Ral-GTPases: good chances for a long-lasting fame. Oncogene 2005;24:326-8.
75. Goi T, Shipitsin M, Lu Z, Foster DA, Klinz SG, Feig LA. An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity. EMBO J 2000;19:623-30.
76. Jiang H, Luo JQ, Urano T, Frankel P, Lu Z, Foster DA, Feig LA. Involvement of Ral GTPase in v-Src-induced phospholipase D activation. Nature 1995;378:409-12.
77. Moskalenko S, Henry DO, Rosse C, Mirey G, Camonis JH, White MA. The exocyst is a Ral effector complex. Nat Cell Biol 2002;4:66-72.
78. Adler HT, Nallaseth FS, Walter G, Tkachuk DC. HRX leukemic fusion proteins form a heterocomplex with the leukemia-associated protein SET and protein phosphatase 2A. J Biol Chem 1997;272:28407-14.
79. Gildea JJ, Harding MA, Seraj MJ, Gulding KM, Theodorescu D. The role of Ral A in epidermal growth factor receptor-regulated cell motility. Cancer Res 2002;62:982-5.
80. Ohta Y, Suzuki N, Nakamura S, Hartwig JH, Stossel TP. The small GTPase RalA targets filamin to induce filopodia. Proc Natl Acad Sci U S A 1999;96:2122-8.
81. Tchevkina E, Agapova L, Dyakova N, Martinjuk A, Komelkov A, Tatosyan A. The small G-protein RalA stimulates metastasis of transformed cells. Oncogene 2005;24:329-35.
82. Panner A, Nakamura JL, Parsa AT, Rodriguez-Viciana P, Berger MS, Stokoe D, Pieper RO. mTOR-independent translational control of the extrinsic cell death pathway by RalA. Mol Cell Biol 2006;26:7345-57.
83. Katoh F, Fitzgerald DJ, Giroldi L, Fujiki H, Sugimura T, Yamasaki H. Okadaic acid and phorbol esters: comparative effects of these tumor promoters on cell transformation, intercellular communication and differentiation in vitro. Jpn J Cancer Res 1990;81:590-7.
84. Sontag E, Fedorov S, Kamibayashi C, Robbins D, Cobb M, Mumby M. The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation. Cell 1993;75:887-97.
85. Li M, Guo H, Damuni Z. Purification and characterization of two potent heat-stable protein inhibitors of protein phosphatase 2A from bovine kidney. Biochemistry 1995;34:1988-96.
86. Katayose Y, Li M, Al-Murrani SW, Shenolikar S, Damuni Z. Protein phosphatase 2A inhibitors, I(1)(PP2A) and I(2)(PP2A), associate with and modify the substrate specificity of protein phosphatase 1. J Biol Chem 2000;275:9209-14.
87. Andersson A, Ritz C, Lindgren D, Eden P, Lassen C, Heldrup J, Olofsson T, Rade J, Fontes M, Porwit-Macdonald A, Behrendtz M, Hoglund M, et al. Microarray-based classification of a consecutive series of 121 childhood acute leukemias: prediction of leukemic and genetic subtype as well as of minimal residual disease status. Leukemia 2007;21:1198-203.
88. Ginos MA, Page GP, Michalowicz BS, Patel KJ, Volker SE, Pambuccian SE, Ondrey FG, Adams GL, Gaffney PM. Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck. Cancer Res 2004;64:55-63.
89. Korkola JE, Houldsworth J, Chadalavada RS, Olshen AB, Dobrzynski D, Reuter VE, Bosl GJ, Chaganti RS. Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors. Cancer Res 2006;66:820-7.
90. Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S, Passaniti A, Menon J, Walling J, Bailey R, Rosenblum M, Mikkelsen T, et al. Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell 2006;9:287-300.
91. Carlson SG, Eng E, Kim EG, Perlman EJ, Copeland TD, Ballermann BJ. Expression of SET, an inhibitor of protein phosphatase 2A, in renal development and Wilms' tumor. J Am Soc Nephrol 1998;9:1873-80.
92. Junttila MR, Li SP, Westermarck J. Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J 2008;22:954-65.
93. Westermarck J, Holmstrom T, Ahonen M, Eriksson JE, Kahari VM. Enhancement of fibroblast collagenase-1 (MMP-1) gene expression by tumor promoter okadaic acid is mediated by stress-activated protein kinases Jun N-terminal kinase and p38. Matrix Biol 1998;17:547-57.
94. Al-Murrani SW, Woodgett JR, Damuni Z. Expression of I2PP2A, an inhibitor of protein phosphatase 2A, induces c-Jun and AP-1 activity. Biochem J 1999;341 ( Pt 2):293-8.
95. Harmala-Brasken AS, Mikhailov A, Soderstrom TS, Meinander A, Holmstrom TH, Damuni Z, Eriksson JE. Type-2A protein phosphatase activity is required to maintain death receptor responsiveness. Oncogene 2003;22:7677-86.
96. Li M, Makkinje A, Damuni Z. The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. J Biol Chem 1996;271:11059-62.
97. Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S, Mao H, Chang JS, Galietta A, Uttam A, Roy DC, Valtieri M, et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell 2005;8:355-68.
98. Adhikary S, Eilers M. Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 2005;6:635-45.
99. Blancato J, Singh B, Liu A, Liao DJ, Dickson RB. Correlation of amplification and overexpression of the c-myc oncogene in high-grade breast cancer: FISH, in situ hybridisation and immunohistochemical analyses. Br J Cancer 2004;90:1612-9.
100. Liao DJ, Dickson RB. c-Myc in breast cancer. Endocr Relat Cancer 2000;7:143-64.
101. Gregory MA, Hann SR. c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt's lymphoma cells. Mol Cell Biol 2000;20:2423-35.
102. Malempati S, Tibbitts D, Cunningham M, Akkari Y, Olson S, Fan G, Sears RC. Aberrant stabilization of c-Myc protein in some lymphoblastic leukemias. Leukemia 2006;20:1572-81.
103. Vervoorts J, Luscher-Firzlaff J, Luscher B. The ins and outs of MYC regulation by posttranslational mechanisms. J Biol Chem 2006;281:34725-9.
104. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 2000;14:2501-14.
105. Sears R, Leone G, DeGregori J, Nevins JR. Ras enhances Myc protein stability. Mol Cell 1999;3:169-79.
106. Arnold HK, Sears RC. Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation. Mol Cell Biol 2006;26:2832-44.
107. Sears RC. The life cycle of C-myc: from synthesis to degradation. Cell Cycle 2004;3:1133-7.
108. Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G, Hahn WC, Stukenberg PT, Shenolikar S, Uchida T, Counter CM, Nevins JR, et al. A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol 2004;6:308-18.
109. Junttila MR, Puustinen P, Niemela M, Ahola R, Arnold H, Bottzauw T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, Lu SL, Lin S, et al. CIP2A inhibits PP2A in human malignancies. Cell 2007;130:51-62.
110. Soo Hoo L, Zhang JY, Chan EK. Cloning and characterization of a novel 90 kDa 'companion' auto-antigen of p62 overexpressed in cancer. Oncogene 2002;21:5006-15.
111. Longin S, Jordens J, Martens E, Stevens I, Janssens V, Rondelez E, De Baere I, Derua R, Waelkens E, Goris J, Van Hoof C. An inactive protein phosphatase
2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator. Biochem J 2004;380:111-9.
112. Ogris E, Du X, Nelson KC, Mak EK, Yu XX, Lane WS, Pallas DC. A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2A. J Biol Chem 1999;274:14382-91.
113. McConnell JL, Gomez RJ, McCorvey LR, Law BK, Wadzinski BE. Identification of a PP2A-interacting protein that functions as a negative regulator of phosphatase activity in the ATM/ATR signaling pathway. Oncogene 2007;26:6021-30.