siRNA干扰突变型p53对泌尿系统肿瘤的治疗作用及其机制研究
|
摘要
野生型p53(wild-type p53,wtp53)是重要的抑癌基因,可诱导细胞周期阻滞、凋亡、分化、静息、DNA损伤、血管生成和转移抑制。多种恶性肿瘤伴有wtp53的错义突变,以及大量突变型p53(mutant p53,mp53)蛋白的聚集。研究表明,wtp53丧失抑癌基因的功能后,一些mp53蛋白将获得新的功能,比如参与肿瘤细胞的增殖,提高肿瘤的化疗耐药性。这些新的变化被称作mp53的获得性功能(mutant p53gain-of-function,mp53GOF).mp53作为肿瘤治疗的一个有效靶点,成为目前肿瘤研究的重要方向之一。研究mp53GOF的重要方法是siRNA干扰试验,siRNA能有效沉默p53基因,排除显性负效应的干扰,为检测与研究mp53GOF提供了有力的技术支持。目前很少有研究探索抑制mp53在泌尿系统肿瘤治疗中的作用。
本研究选择泌尿系统中的膀胱癌与前列腺癌作为研究对象。前者是我国发病率最高的泌尿系统恶性肿瘤,后者去势抵抗前列腺癌的治疗为临床难点。针对前列腺癌细胞株DU145、膀胱癌细胞株T24、5637,我们使用siRNA干扰技术,研究靶向mp53的siRNA对细胞生长、凋亡、以及化疗耐药性的影响,评估其治疗应用的可行性。主要研究内容及成果如下：
1.mp53干扰后,体外细胞培养及RT-PCR检测发现：前列腺癌DU145、膀胱癌T24、5637细胞的mp53表达明显降低,p53-siRNA能有效抑制肿瘤细胞的生长和活力。MTT实验发现抑制作用呈时间一剂量依赖性。
2.流式细胞术以及蛋白印记实验结果表明：干扰mp53后,DU145细胞阻滞在G1和G2期,而膀胱癌T24、5637表现为G2期细胞周期阻滞。同时,p53-siRNA具有较强的凋亡诱导能力,其诱导的凋亡可能与Bcl-2家族蛋白相关。
3.mp53沉默后PI3K/Akt抗凋亡信号通路受到了抑制,可能是引起细胞凋亡和周期阻滞的作用机制之一。
4.MTT法和流式细胞术结果提示p53-siRNA与cisplatin联用较两者单用更能明显抑制膀胱癌5637细胞活性,两者对抑制细胞存活率具有协同作用。
总之,siRNA靶向抑制mp53或许能成为治疗泌尿系统肿瘤的一种有效手段,对于去势抵抗前列腺癌以及耐药性膀胱癌具有一定的治疗效果和应用前景。该技术也可以应用于其它具有mp53的恶性肿瘤研究与治疗中。但是,在临床应用之前,还需要进行进一步探索和验证,包括机理研究与动物实验等。
Wild-type p53(wtp53) is a major tumor suppressor whose function is critical for protection against cancer. It has been reported that wtp53can induce cell cycle arrest、DNA damage、angiogenesis and metastasis inhibition. Many human tumors carry missense mutations in the p53gene and the affected tumor cells accumulate excessive amounts of the mutant p53(mp53) protein. Various lines of evidence indicate that, in addition to abrogating the tumor suppressor functions of wtp53, the common types of cancer-associated p53mutations also endow the mutant protein with new activities that can contribute actively to various stages of tumor progression and to increased resistance to anticancer treatments. Collectively, these activities are referred to as mp53gain-of-function(mp53GOF). At present, the research on mp53becomes increasingly important as a valid target for inactivation by prospective anticancer therapies. An effective approach to explore mp53GOF, which has become feasible by the advent of siRNA technology, relies on knocking down endogenous mp53in tumor derived cells. It is suitable for monitoring the changes in cell phenotype while excluding dominant-negative effects over wtp53. However, the researches on its distinctive roles in the urogenital cancers are rare.
This paper focused on the mp53GOF in prostatic cancer and bladder cancer. Chemotherapy was thought to have minimal clinical efficacy in men with metastatic, hormone-refractory prostate cancer and drug resistant bladder cancer. Therefore, novel therapeutic strategies for the treatment are urgently required. In this study, we knocked down the endogenous mp53in DU145human androgen-independent prostate cancer cell line and T24、5637bladder cancer cells with the siRNA technology, analyzed the outcomes of cells growth, viability, apoptosis and drug resistance, evaluates its therapeutic potential.
The main investigations and results are as follows:
1. Expressions of mp53mRNA and protein were down-regulated significantly in cell lines DU145、T24and5637after siRNA transfections which were detected by real-time RT-PCR and Western blotting. Knockdown of mp53inhibits cells growth and viability and this phenomenon was concentration and time-dependent demonstrated by MTT assay.
2. The impact of silencing mutant p53on cell cycle and apoptosis was examined by flow-cytometric analysis of cells labeled by PI and annexin V, and the related proteins of cell cycle and apoptosis were detected by Western blotting. p53-siRNA induced the arrest of cell proliferation at the both G1and G2phase in DU145cells while induced G2-phase cell cycle arrest in5637and T24cells. The p53-siRNA could also induce remarkable apoptosis in these cell lines and it maybe occurs with the involvement of Bcl-2family pathway.
3. Suppression of p53mutants by siRNA resulted in attenuation of PI3K/Akt pathway., which might be one of the mechanisms related to the effects of p53-siRNA.
4. Silence of mp53by siRNA increased responsiveness to chemotherapeutic cisplatin in5637cells by MTT assay and flow-cytometric analysis. They exhibited a characteristic of synergic action to reduce the cells viability.
In conclution, suppression of p53mutants by siRNA could be an effective and important technology in the treatment of urogenital cancers, especially for treating the hormone-refractory prostate cancer and the drug resistant bladder cancer. Meanwhile, our study also provided evidence and basis for its future clinical application in the therapeutics of other cancer with mutant p53. However, there are still a lot of problems need to be investigated and improved, including the exact mechanisms and in vivo therapeutic experiments.
本研究选择泌尿系统中的膀胱癌与前列腺癌作为研究对象。前者是我国发病率最高的泌尿系统恶性肿瘤,后者去势抵抗前列腺癌的治疗为临床难点。针对前列腺癌细胞株DU145、膀胱癌细胞株T24、5637,我们使用siRNA干扰技术,研究靶向mp53的siRNA对细胞生长、凋亡、以及化疗耐药性的影响,评估其治疗应用的可行性。主要研究内容及成果如下：
1.mp53干扰后,体外细胞培养及RT-PCR检测发现：前列腺癌DU145、膀胱癌T24、5637细胞的mp53表达明显降低,p53-siRNA能有效抑制肿瘤细胞的生长和活力。MTT实验发现抑制作用呈时间一剂量依赖性。
2.流式细胞术以及蛋白印记实验结果表明：干扰mp53后,DU145细胞阻滞在G1和G2期,而膀胱癌T24、5637表现为G2期细胞周期阻滞。同时,p53-siRNA具有较强的凋亡诱导能力,其诱导的凋亡可能与Bcl-2家族蛋白相关。
3.mp53沉默后PI3K/Akt抗凋亡信号通路受到了抑制,可能是引起细胞凋亡和周期阻滞的作用机制之一。
4.MTT法和流式细胞术结果提示p53-siRNA与cisplatin联用较两者单用更能明显抑制膀胱癌5637细胞活性,两者对抑制细胞存活率具有协同作用。
总之,siRNA靶向抑制mp53或许能成为治疗泌尿系统肿瘤的一种有效手段,对于去势抵抗前列腺癌以及耐药性膀胱癌具有一定的治疗效果和应用前景。该技术也可以应用于其它具有mp53的恶性肿瘤研究与治疗中。但是,在临床应用之前,还需要进行进一步探索和验证,包括机理研究与动物实验等。
Wild-type p53(wtp53) is a major tumor suppressor whose function is critical for protection against cancer. It has been reported that wtp53can induce cell cycle arrest、DNA damage、angiogenesis and metastasis inhibition. Many human tumors carry missense mutations in the p53gene and the affected tumor cells accumulate excessive amounts of the mutant p53(mp53) protein. Various lines of evidence indicate that, in addition to abrogating the tumor suppressor functions of wtp53, the common types of cancer-associated p53mutations also endow the mutant protein with new activities that can contribute actively to various stages of tumor progression and to increased resistance to anticancer treatments. Collectively, these activities are referred to as mp53gain-of-function(mp53GOF). At present, the research on mp53becomes increasingly important as a valid target for inactivation by prospective anticancer therapies. An effective approach to explore mp53GOF, which has become feasible by the advent of siRNA technology, relies on knocking down endogenous mp53in tumor derived cells. It is suitable for monitoring the changes in cell phenotype while excluding dominant-negative effects over wtp53. However, the researches on its distinctive roles in the urogenital cancers are rare.
This paper focused on the mp53GOF in prostatic cancer and bladder cancer. Chemotherapy was thought to have minimal clinical efficacy in men with metastatic, hormone-refractory prostate cancer and drug resistant bladder cancer. Therefore, novel therapeutic strategies for the treatment are urgently required. In this study, we knocked down the endogenous mp53in DU145human androgen-independent prostate cancer cell line and T24、5637bladder cancer cells with the siRNA technology, analyzed the outcomes of cells growth, viability, apoptosis and drug resistance, evaluates its therapeutic potential.
The main investigations and results are as follows:
1. Expressions of mp53mRNA and protein were down-regulated significantly in cell lines DU145、T24and5637after siRNA transfections which were detected by real-time RT-PCR and Western blotting. Knockdown of mp53inhibits cells growth and viability and this phenomenon was concentration and time-dependent demonstrated by MTT assay.
2. The impact of silencing mutant p53on cell cycle and apoptosis was examined by flow-cytometric analysis of cells labeled by PI and annexin V, and the related proteins of cell cycle and apoptosis were detected by Western blotting. p53-siRNA induced the arrest of cell proliferation at the both G1and G2phase in DU145cells while induced G2-phase cell cycle arrest in5637and T24cells. The p53-siRNA could also induce remarkable apoptosis in these cell lines and it maybe occurs with the involvement of Bcl-2family pathway.
3. Suppression of p53mutants by siRNA resulted in attenuation of PI3K/Akt pathway., which might be one of the mechanisms related to the effects of p53-siRNA.
4. Silence of mp53by siRNA increased responsiveness to chemotherapeutic cisplatin in5637cells by MTT assay and flow-cytometric analysis. They exhibited a characteristic of synergic action to reduce the cells viability.
In conclution, suppression of p53mutants by siRNA could be an effective and important technology in the treatment of urogenital cancers, especially for treating the hormone-refractory prostate cancer and the drug resistant bladder cancer. Meanwhile, our study also provided evidence and basis for its future clinical application in the therapeutics of other cancer with mutant p53. However, there are still a lot of problems need to be investigated and improved, including the exact mechanisms and in vivo therapeutic experiments.
引文
1. Soussi T, Beroud C. Assessing Tp53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer,2001,1:233-240.
2. Fang Chen, Wenge Wang, Wafik S. El-Deiry. Current strategies to target p53 in cancer. Bio Phar,2010,80:724-730.
3. Song H, Hollstein M, Xu Y. p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. Nat Cell Biol,2007,9:573-580.
4. Kalo E, Buganim Y, Shapira KE, Besserglick H, Goldfinger N, Weisz L, Stambolsky P, Henis YI, Rotter V. Mutant p53 attenuates the SMAD—dependent transforming growth factor beta I(TGF—beta I)signaling pathway by repressing the expression of TGF—beta receptor type II. Mol Cell Biol,2007,27:8228-8242.
5. A. Fire, S. Xu, M.K. Montgomery, S.A. Kostas, S.E. Driver, and C.C. Mello, Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature,1998,391(6669):806-11.
6. Ashihara E, Kawata E, Maekawa T. Future prospect of RNA interference for cancer therapies. Curr Drug Targets,2010,11(3):345360.
7. Merritt WM, Bar Eli M, Sood AK. The dicey role of Dicer:implications for RNAi therapy. Cancer Res,2010,70:2571-2574.
8. Phalon C, Rao DD, and Nemunaitis J, Potential use of RNA interference in cancer therapy. Expert Rev Mol Med,2010,12:e26.
9. Takeshita F and Ochiya T, Therapeutic potential of RNA interference against cancer. Cancer Sci,2006,97:689-96.
10. Heidenreich A, Aus G, Bolla M, Joniau S, Matveev VB, Schmid HP, and Zattoni F, EAU guidelines on prostate cancer. Eur Urol,2008,53(1):68-80.
11. Wolff JM, Chemotherapy in hormone-refractory prostate cancer. Front Radiat Ther Oncol,2008,41:103-7.
12. Bookstein R, MacGrogan D, Hilsenbeck SG, Sharkey F, and Allred DC, p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res,1993,53: 3369-73.
13. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics,2010. CA Cancer J Clin.2010 60(5):277-300.
14. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med.2003; 349:859-66.
15. Splinter TA, Scher HI, Denis L, et al. European Organization for Research on Treatment of Cancer-Genitourinary Group. The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. J Urol.1992; 147:606-8.
16. Vaughn DJ. Review and outlook for the role of paclitaxel in urothelial carcinoma. Semin Oncol.1999; 26:117-22.
1. Lane D and Levine A, p53 Research:the past thirty years and the next thirty years. Cold Spring Harb Perspect Biol,2010,2(12):a00O893.
2. Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, White R, and Vogelstein B, Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science,1989,244(4901):217-21.
3. Levine AJ, Momand J, and Finlay CA, The p53 tumour suppressor gene. Nature, 1991,351(6326):453-6.
4. Soussi T and Beroud C, Assessing Tp53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer,2001,1(3):233-40.
5. Goh AM, Coffill CR, and Lane DP, The role of mutant p53 in human cancer. J Pathol,2011,223(2):116-26.
6. Strano S, Dell'Orso S, Mongiovi AM, Monti O, Lapi E, Di Agostino S, Fontemaggi G, and Blandino G, Mutant p53 proteins:between loss and gain of function. Head Neck,2007,29(5):488-96.
7. Kastan MB and Berkovich E, p53:a two-faced cancer gene. Nat Cell Biol,2007, 9(5):489-91.
8. Oren M and Rotter V, Mutant p53 gain-of-function in cancer. Cold Spring Harb Perspect Biol,2010,2(2):a001107.
9. Navone NM, Troncoso P, Pisters LL, Goodrow TL, Palmer JL, Nichols WW, von Eschenbach AC, and Conti CJ, p53 protein accumulation and gene mutation in the progression of human prostate carcinoma. J Natl Cancer Inst,1993,85(20): 1657-69.
10. Perryman LA, Blair JM, Kingsley EA, Szymanska B, Ow KT, Wen VW, MacKenzie KL, Vermeulen PB, Jackson P, and Russell PJ, Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo. Biochem Biophys Res Commun,2006,345(3):1207-14.
11. Che M, DeSilvio M, Pollack A, Grignon DJ, Venkatesan VM, Hanks GE, and Sandier HM, Prognostic value of abnormal p53 expression in locally advanced prostate cancer treated with androgen deprivation and radiotherapy:a study based on RTOG 9202. Int J Radiat Oncol Biol Phys,2007,69(4):1117-23.
12. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, and Mello CC, Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature,1998,391(6669):806-11.
13. Rychahou PG, Jackson LN, Farrow BJ, and Evers BM, RNA interference: mechanisms of action and therapeutic consideration. Surgery,2006,140(5): 719-25.
14. Angaji SA, Hedayati SS, Poor RH, Madani S, Poor SS, and Panahi S, Application of RNA interference in treating human diseases. J Genet,2010, 89(4):527-37.
15. Phalon C, Rao DD, and Nemunaitis J, Potential use of RNA interference in cancer therapy. Expert Rev Mol Med,2010,12:e26.
16. Takeshita F and Ochiya T, Therapeutic potential of RNA interference against cancer. Cancer Sci,2006,97(8):689-96.
17. Efeyan A and Serrano M, p53:guardian of the genome and policeman of the oncogenes. Cell Cycle,2007,6(9):1006-10.
18. Heidenreich A, Aus G, Bolla M, Joniau S, Matveev VB, Schmid HP, and Zattoni F, EAU guidelines on prostate cancer. Eur Urol,2008,53(1):68-80.
19. Wolff JM, Chemotherapy in hormone-refractory prostate cancer. Front Radiat Ther Oncol,2008,41:103-7.
20. Takei Y, Kadomatsu K, Yuzawa Y, Matsuo S, and Muramatsu T, A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res,2004,64(10):3365-70.
21. Lee SO, Lou W, Qureshi KM, Mehraein-Ghomi F, Trump DL, and Gao AC, RNA interference targeting Stat3 inhibits growth and induces apoptosis of human prostate cancer cells. Prostate,2004,60(4):303-9.
22. De Schrijver E, Brusselmans K, Heyns W, Verhoeven G, and Swinnen JV, RNA interference-mediated silencing of the fatty acid synthase gene attenuates growth and induces morphological changes and apoptosis of LNCaP prostate cancer cells. Cancer Res,2003,63(13):3799-804.
23. Bullock AN and Fersht AR, Rescuing the function of mutant p53. Nat Rev Cancer,2001,1(1):68-76.
24. Maslon MM and Hupp TR, Drug discovery and mutant p53. Trends Cell Biol, 2010,20(9):542-55.
25. Ma LL, Sun WJ, Wang Z, Zh GY, Li P, and Fu SB, Effects of silencing of mutant p53 gene in human lung adenocarcinoma cell line Anip973. J Exp Clin Cancer Res,2006,25(4):585-92.
26. Sarker D, Reid AH, Yap TA, and de Bono JS, Targeting the PI3K/AKT pathway for the treatment of prostate cancer. Clin Cancer Res,2009,15(15):4799-805.
27. Yonesaka K, Tamura K, Kurata T, Satoh T, Ikeda M, Fukuoka M, and Nakagawa K, Small interfering RNA targeting survivin sensitizes lung cancer cell with mutant p53 to adriamycin. Int J Cancer,2006,118(4):812-20.
28. Niu J, Xu Z, Li XN, and Han Z, siRNA-mediated type 1 insulin-like growth factor receptor silencing induces chemosensitization of a human liver cancer cell line with mutant p53. Cell Biol Int,2007,31(2):156-64.
29. Bookstein R, MacGrogan D, Hilsenbeck SG, Sharkey F, and Allred DC, p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res,1993, 53(14):3369-73.
30. Downing S, Bumak C, Nixdorf S, Ow K, Russell P, and Jackson P, Elevated levels of prostate-specific antigen (PSA) in prostate cancer cells expressing mutant p53 is associated with tumor metastasis. Mol Carcinog,2003,38(3): 130-40.
31. Strano S, Dell'Orso S, Di Agostino S, Fontemaggi G, Sacchi A, and Blandino G, Mutant p53:an oncogenic transcription factor. Oncogene,2007,26(15):2212-9.
32. Li Y and Prives C, Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function? Oncogene,2007,26(15):2220-5.
33. Ghosh PM, Malik S, Bedolla R, and Kreisberg JI, Akt in prostate cancer: possible role in androgen-independence. Curr Drug Metab,2003,4(6):487-96.
34. Rege YD and Rangnekar VM, Molecular therapy intervention prospects in prostate cancer. Curr Pharm Des,2004,10(5):523-30.
35. Dong P, Xu Z, Jia N, Li D, and Feng Y, Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway. Mol Cancer, 2009,8:103.
36. Gesbert F, Sellers WR, Signoretti S, Loda M, and Griffin JD, BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27Kip1 through the phosphatidylinositol 3-Kinase/AKT pathway. J Biol Chem,2000,275(50): 39223-30.
37. Diehl JA, Cheng M, Roussel MF, and Sherr CJ, Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev,1998, 12(22):3499-511.
38. Boise LH, Gottschalk AR, Quintans J, and Thompson CB, Bcl-2 and Bcl-2-related proteins in apoptosis regulation. Curr Top Microbiol Immunol, 1995,200:107-21.
1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics,2010. CA Cancer J Clin.2010 60(5):277-300.
2. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med.2003; 349:859-66.
3. Splinter TA, Scher HI, Denis L, et al. European Organization for Research on Treatment of Cancer-Genitourinary Group. The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. J Urol.1992; 147:606-8.
4. Vaughn DJ. Review and outlook for the role of paclitaxel in urothelial carcinoma. Semin Oncol.1999; 26:117-22.
5. Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature 2009.458:1127-1130.
6. Vousden KH, Prives C. Blinded by the light:the growing complexity of p53. Cell 2009.137:413-431.
7. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991,253,49-53.
8. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000,408, 307-310.
9. Kato, S. et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc. Natl Acad. Sci. USA.2003,100,8424-9.
10. Milner J, Medcalf EA, Cook AC. Tumor suppressor p53:analysis of wild-type and mutant p53 complexes. Mol. Cell Biol.1991,11,12-19.
11. Milner J, Medcalf EA. Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation. Cell 1991,65,65-74.
12. Oren M, Rotter V. Mutant p53 Gain-of-Function in Cancer. Cold Spring Harb Perspect Biol 2010; 2:a001107.
13. Bossi, G. et al. Mutant p53 gain of function:reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene 2006,25,304-309.
14. Bossi, G. et al. Conditional RNA interference in vivo to study mutant p53 oncogenic gain of function on tumor malignancy. Cell Cycle.2008,7,1870-9.
15. Mitra AP, Datar RH, Cote RJ. Molecular pathways in invasive bladder cancer:New insights into mechanisms, progression, and target identification. J Clin Oncol.2006, 24:5552-5564. doi:10.1200/JCO.2006.08.2073.
16. Bakkar AA, Wallerand H, Radvanyi F, Lahaye JB, Pissard S, Lecerf L, Kouyoumdjian JC, Abbou CC, Pairon JC, Jaurand MC, Thiery JP, Chopin DK, de Medina SG. FGFR3 and Tp53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res.2003,63:8108-12.
17. Nishiyama H, Watanabe J, Ogawa O. p53 and chemosensitivity in bladder cancer. Int J Clin Oncol.2008,13:282-6.
18. Cooper MJ, Haluschak JJ, Johnson D, Schwartz S, Morrison LJ, Lippa M, Hatzivassiliou G and Tan J:p53 mutations in bladder carcinoma cell lines. Oncol Res,1994,6:569-579.
19. Riegerl KM, Little AF, Swart JM, Kastrinakis WV, Fitzgerald JM, Hess DT, Libertino JA, Summerhayes IC. Human bladder carcinoma cell lines as indicators of oncogenic change relevant to urothelial neoplastic progression. British Journal of Cancer.1995,72,683-690.
20. Weisz L, Oren M, Rotter V. Transcription regulation by mutant p53. Oncogene. 2007,26,2202-2211.
21. Donzelli, S. et al. Oncogenomic approaches in exploring gain of function of mutant p53. Curr. Genomics.2008,9,200-7.
22.张薇,项永兵,刘振伟,方茹蓉,阮志贤,孙璐,高立峰,金凡,高玉堂.1973-1999年上海市区老年人恶性肿瘤发病趋势分析.中华老年医学杂志,2005,24(9)：701-4.
23. Menendez D, Inga A, Resnick MA. The expanding universe of p53 targets. Nat Rev Cancer. Nat Rev Cancer.2009; 9(10):724-37.
24. Blandino G, Levine AJ, Oren M. Mutant p53 gain of function:differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene. 1999; 18:477-85.
25. Li R, Sutphin PD, Schwartz D, Matas D, Almog N, et al. Mutant p53 protein expression interferes with p53-independent apoptotic pathways. Oncogene.1998; 16: 3269-77.
26. Bergamaschi D, Gasco M, Hiller L, Sullivan A, Syed N, et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell.2003; 3:387-402.
27. Wolf D, Harris N, Rotter V. Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene. Cell.1984; 38:119-26.
28. Bumcrot D, Manoharan M, Koteliansky V, et al. RNAi therapeutics:a potential new class of pharmaceutical drugs. Nat. Chem. Biol.2006.2(12):711-9.
29. Castanotto D, Rossi JJ. The promises and pitfalls of RNA-interference-based therapeutics. Nature.2009,457(7228):426-33.
30. Ma LL, Sun WJ, Wang Z, Zh GY, Li P, et al. Effects of silencing of mutant p53 gene in human lung adenocarcinoma cell line Anip973. J Exp Clin Cancer Res.2006; 25: 585-92.
31. Zhu H, Mao Q, Lin Y, Yang K, Xie L. RNA interference targeting mutant p53 inhibits growth and induces apoptosis in DU145 human prostate cancer cells. Med Oncol.2010 Sep 21. [Epub ahead of print]
32. Hwang A, Muschell RJ. Radiation and the G2 phase of the cell cycle. Radiat. Res. 1998.150, S52-9.
33. Innocente SA, Abrahamson JLA, Cogswell JP, Lee JM. p53 regulates a G2 checkpoint through cyclin B1. Proc. Natl. Acad. Sci. USA.1999.96,2147-52.
34. Pagano M, Pepperkok R, Verde F, Ansorge W, Draetta G. Cyclin A is required at two points in the human cell cycle. EMBO. J.1992,11; 961-71.
35. Salvesen GS, Dixit VM. Caspase activation:the inducedproximity model. Proc Natl Acad Sci USA.1999; 96:10964-7.
36. Germain M, Affar EB, D'Amours D, et al. Cleavage of automodified poly (ADP-ribose) polymerase during apoptosis:evidence for involvement of caspase-7. J Biol Chem.1999; 274:28379-84.
37. Ivana Scovassi A, Diederich M. Modulation of poly (ADPribosylation) in apoptotic cells. Biochem Pharmacol.2004; 68:1041-7.
38. Lehmann J, Retz M, Stockle M. Chemotherapy in the post-MVAC era:the case for adjuvant chemotherapy. World J Urol.2002.20:144-50.
39. Ardavanis A, Tryfonopoulos D, Alexopoulos A, Kandylis C, Lainakis G, Rigatos G. Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase Ⅱ study. Br J Cancer.2005.92:645-50.
40. Rosenberg JE, Carroll PR, Small EJ. Update on chemotherapy for advanced bladder cancer. J Urology.2005.174:14-20.
41. Theodore C, Geoffrois L, Vermorken JB, Caponigro F, Fiedler W, Chollet P, et al. Multicentre EORTC study 16997:feasibility and phase Ⅱ trial of farnesyl transferase inhibitor & gemcitabine combination in salvage treatment of advanced urothelial tract cancers. Eur J Cancer.2005.41:1150-7.
42. Cote RJ, Esrig D, Groshen S, et al. p53 and treatment of bladder cancer. Nature. 1997,385:123-124
43. Watanabe J, Nishiyama H, Okubo K, et al. Clinical evaluation of p53 mutations in urothelial carcinoma by IHC and FASAY. Urology.2004,63:989-93.
44. Bergh J, Norberg T, Sjogren S, Lindgren A, Holmberg L. Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nature Med.1995,1, 1029-34.
45. Aas, T. et al. Specific p53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nature Med.1996,2,811-4.
46. Blandino G, Levine AJ, Oren M. Mutant p53 gain of function:differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene, 1999,18,477-85.
47. Lu C, El-Deiry WS. Targeting p53 for enhanced radio-and chemo-sensitivity. Apoptosis,2009,14,597-606.
48. Chin KV, Ueda K, Pastan I, Gottesman MM. Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. Science.1992,255,459-62.
49. Bush JA, Li G. Cancer chemoresistance:the relationship between p53 and multidrug transporters. Int. J. Cancer.2002,98,323-30.
50. Li R, et al. Mutant p53 protein expression interferes with p53-independent apoptotic pathways. Oncogene,1998,16,3269-77.
1. Rotter V. p53, a transformation-related cellularencoded protein, can be used as a biochemical marker for the detection of primary mouse tumor cells. Proc Natl Acad Sci,1983,80:2613-2617.
2. Michalovitz D, Halevy O, Oren M. p53 mutations:gains or losses? J Cell Bioch, 1991,45:22-29.
3. Sigal A, Rotter V. Oncogenic mutations of the p53 tumor suppressor:The demons of the guardian of the genome. Cancer Res,2000,60:6788-6793.
4. Weisz L, Oren M, Rotter V. Transcription regulation by mutant p53. Oncogene, 2007b,26:2202-2211.
5. Brosh R, Rotter V.2009. When mutants gain new powers:news from the mutant p53 field. Nature Rev Cancer,2009,9:701-13.
6. Donzelli S, Biagioni F, Fausti F, Strano S, Fontemaggi G,Blandino G. Oncogenomic Approaches in Exploring Gain of Function of Mutant p53. Current Genomics,2008, 9:200-207.
7. Lozano G. The oncogenic roles of p53 mutants in mouse models. Current opinion in genetics&development,2007,17:66-70.
8. Olivier M, Petitjean A, Marcel V, Petre A, Mounawar M,Plymoth A, de Fromentel CC, Hainaut P. Recent advances in p53 research:An interdisciplinary perspective.Cancer Gene Therapy,2009,16:1-12.
9. DittmerD, Pati S, Zambetti G, Chu S, Teresky AK,MooreM, Finlay C, Levine AJ. Gain of function mutations in p53. Nature Genetics,1993,4:42-46.
10. Levine AJ, Oren M. The first 30 years of p53:growing ever more complex. Nat Rev Cancer,2009,9:749-758.
11. Wolf D, Harris N, Rotter V. Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene. Cell,1984, 38:119-126.
12. Chin KV, Ueda K, Pastan I, Gottesman MM. Modulation of activity of the promoter of the humanMDR1gene by Ras and p53. Science,1992,255:459-462.
13. Deb S, Jackson CT, Subler MA, Martin DW. Modulation of cellular and viral promoters by mutant human p53 proteins found in tumor cells. J Virol,1992,66: 6164-6170.
14. Matas D, Sigal A, Stambolsky P, Milyavsky M, Weisz L, Schwartz D, Goldfinger N, Rotter V. Integrity of the N-terminal transcription domain of p53 is required for mutant p53 interference with drug-induced apoptosis. Embo J,2001,20: 4163-4172.
15. Gualberto A, Aldape K, Kozakiewicz K, Tlsty TD. An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Proc Natl Acad Sci USA,1998,95:5166-5171.
16. Iwamoto KS, Mizuno T, Ito T, Tsuyama N, Kyoizumi S, Seyama T. Gain-of-function p53 mutations enhance alteration of the T-cell receptor following X-irradiation, independently of the cell cycle and cell survival. Cancer Res,1996,56: 3862-3865.
17. Murphy KL, Dennis AP, Rosen JM. A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model. Faseb J,2000,14:2291-2302.
18. El-Hizawi S, Lagowski JP, Kulesz-Martin M, Albor A. Induction of gene amplification as a gain-of-function phenotype of mutant p53 proteins. Cancer Res, 2002,62:3264-3270.
19. Caulin C, Nguyen T, Lang GA, Goepfert TM, Brinkley BR, CaiWW, Lozano G, Roop DR. An inducible mouse model for skin cancer reveals distinct roles for gainand loss-of-function p53 mutations. J Clin Invest,2007,117:1893-1901.
20. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell,2005,7:469-483.
21.Talos F, Nemajerova A, Flores ER, Petrenko O, Moll UM. p73 suppresses polyploidy and aneuploidy in the absence of functional p53. Molecular Cell,2007, 27:647-659.
22. Offer H, Wolkowicz R, Matas D, Blumenstein S, Livneh Z, Rotter V. Direct involvement of p53 in the base excision repair pathway of the DNA repair machinery. FEBS Lett,1999,450:197-204.
23. Lotem J, Sachs L. Amutant p53 antagonizes the deregulated c-myc-mediated enhancement of apoptosis and decrease in leukemogenicity. Proc Natl Acad Sci USA,1995,92:9672-9676.
24. Peled A, Zipori D, Rotter V. Cooperation between p53-dependent and p53-independent apoptotic pathways in myeloid cells. Cancer Res,1996,56: 2148-2156.
25. Li R, Sutphin PD, Schwartz D, Matas D, Almog N, Wolkowicz R, Goldfinger N, Pei H, Prokocimer M, Rotter V. Mutant p53 protein expression interferes with p53-independent apoptotic pathways. Oncogene,1998,16:3269-3277.
26. Blandino G, Levine AJ, Oren M. Mutant p53 gain of function:differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene, 1999,18:477-485.
27. Yap DB, Hsieh JK, Zhong S, Heath V, Gusterson B, Crook T,Lu X. Ser392 phosphorylation regulates the oncogenic function of mutant p53. Cancer Res,2004, 64:4749-4754.
28. Vikhanskaya F, LeeMK, MazzolettiM, BrogginiM, Sabapathy K. Cancer-derived p53 mutants suppress p53-target gene expression-potential mechanism for gain of function of mutant p53. Nucleic Acids Res,2007,35:2093-2104.
29. Weisz L, Damalas A, Liontos M, Karakaidos P, Fontemaggi G, Maor-Aloni R, Kalis M, LevreroM, Strano S, Gorgoulis VG, et al. Mutant p53 enhances nuclear factor kappaB activation by tumor necrosis factor a in cancer cells. Cancer Res,2007a,67: 2396-2401.
30. Wong RP, Tsang WP, Chau PY, Co NN, Tsang TY, Kwok TT. p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3. Molecular Cancer Therapeutics,2007,6:1054-1061.
31. Bossi G, Lapi E, Strano S, Rinaldo C, Blandino G, Sacchi A. Mutant p53 gain of function:reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene,2006,25:304-309.
32. Olivier M, Hollstein M, Hainaut P. Tp53 mutations in human cancers:origins, consequences, and clinical use.Cold Spring Harb Perspect Biol,2010,2:a001008.
33. Vogelstein B, Kinzler KW. The multistep nature of cancer.Trends Genet,1993,9: 138-141.
34. Adorno M, Cordenonsi M,Montagner M, Dupont S,Wong C, Hann B, Solari A, Bobisse S, Rondina MB, Guzzardo V, et al. AMutant-p53/Smad complex opposes p63 to empower TGFb-induced metastasis. Cell,2009,137:87-98.
35. Wang SP, Wang WL, Chang YL, Wu CT, Chao YC, Kao SH,Yuan A, Lin CW, Yang SC, Chan WK, et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol,2009,11:694-704.
36. Buganim Y, Kalo E, Brosh R, Besserglick H, Nachmany I,Rais Y, Stambolsky P, Tang X, Milyavsky M, Shats I,et al. Mutant p53 protects cells from 12-Otetradecanoylphorbol-13-acetate-induced death by attenuating activating transcription factor 3 induction. Cancer Res,2006,66:10750-10759.
37. Dong P, Tada M, Hamada J, Nakamura A, Moriuchi T,Sakuragi N. p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells. Clin Exp Metastasis,2007,24:471-483.
38. Kalo E, Buganim Y, Shapira KE, Besserglick H, Goldfinger N, Weisz L, Stambolsky P, Henis YI, Rotter V. Mutant p53 attenuates the SMAD-dependent transforming growth factor b1 (TGF-b1) signaling pathway by repressing the expression of TGF-b receptor type II.Mol Cell Biol,2007,27:8228-8242.
39. Derynck R, Akhurst RJ, Balmain A. TGF-b signaling in tumor suppression and cancer progression. Nature Genetics,2001,29:117-129.
40. Massague J. TGF β in Cancer. Cell,2008,134:215-230.
41. Hsiao M, Low J, Dorn E, Ku D, Pattengale P, Yeargin J, Haas M. Gain-of-function mutations of the p53 gene induce lymphohematopoietic metastatic potential and tissue invasiveness. Am J Pathol,1994,145:702-14.
42. Lanyi A, Deb D, Seymour RC, Ludes-Meyers JH, Subler MA, Deb S.'Gain of function'phenotype of tumor-derived mutant p53 requires the oligomerization/nonsequence-specific nucleic acid-binding domain.Oncogene, 1998,16:3169-3176.
43. Duan W, Ding H, Subler MA, Zhu WG, Zhang H, Stoner GD, Windle JJ, Otterson GA, Villalona-Calero MA. Lung-specific expression of human mutant p53-273H is associated with a high frequency of lung adenocarcinoma in transgenic mice. Oncogene,2002,21:7831-7838.
44. Duan W, Gao L, Wu X, Hade EM, Gao JX, Ding H, Barsky SH, Otterson GA, Villalona-Calero MA. Expression of a mutant p53 results in an age-related demographic shift in spontaneous lung tumor formation in transgenic mice. PloS One,2009,4:e5563.
45. Heinlein C, Krepulat F, Lohler J, Speidel D, Deppert W.Tolstonog GV. Mutant p53 (R270H) gain of function phenotype in a mouse model for oncogeneinduced mammary carcinogenesis. Int J Cancer,2008,122:1701-1709.
46. Pohl J, Goldfinger N, Radler-Pohl A, Rotter V, Schirrmacher V. p53 increases experimental metastatic capacity of murine carcinoma cells. Mol Cell Biol,1988,8: 2078-2081.
47. Bossi G,Marampon F,Maor-Aloni R, Zani B, Rotter V, Oren M, Strano S, Blandino G, Sacchi A. Conditional RNA interference in vivo to study mutant p53 oncogenic gain of function on tumor malignancy. Cell Cycle (Georgetown, Tex),2008,7: 1870-1879.
48. Lang GA, Iwakuma T, Suh YA, Liu G, Rao VA, Parant JM, Valentin-Vega YA, Terzian T, Caldwell LC, Strong LC, et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell,2004,119:861-872.
49. Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, CrowleyD, Jacks T. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell, 2004,119:847-860.
50. Caulin C, Nguyen T, Lang GA, Goepfert TM, Brinkley BR,CaiWW, Lozano G, Roop DR. An inducible mouse model for skin cancer reveals distinct roles for gainand loss-of-function p53 mutations. J Clin Invest,2007,117:1893-1901.
51. Joerger AC, Fersht AR. Structural biology of the tumor suppressor p53. Annual review of biochemistry,2008,77:557-582.
52. Chin KV, Ueda K, Pastan I, Gottesman MM. Modulation of activity of the promoter of the humanMDR1gene by Ras and p53. Science,1992,255:459-462.
53. Frazier MW, He X, Wang J, Gu Z, Cleveland JL, Zambetti GP. Activation of c-myc gene expression by tumorderived p53 mutants requires a discrete C-terminal domain. Mol Cell Biol,1998,18:3735-3743.
54. Lee YI, Lee S, Das GC, Park US, Park SM, Lee YI. Activation of the insulin-like growth factor Ⅱ transcription by aflatoxin B1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma. Oncogene,2000,19:3717-3726.
55. Singer S, Ehemann V, Brauckhoff A, Keith M, Vreden S,Schirmacher P, Breuhahn K. Protumorigenic overexpression of stathmin/Opl8 by gain-of-function mutation in p53 in human hepatocarcinogenesis. Hepatology (Baltimore, Md),2007,46: 759-768.
56. Lavra L, Ulivieri A, Rinaldo C, Dominici R, Volante M, Luciani E, Bartolazzi A, Frasca F, Soddu S, Sciacchitano S. Gal-3 is stimulated by gain-of-function p53 mutations and modulates chemoresistance in anaplastic thyroid carcinomas. J Pathol, 2009,218:66-75.
57. Brosh R, Rotter V. When mutants gain new powers:news from the mutant p53 field. Nature Rev Cancer,2009,9:701-713.
58. Beckerman R, Prives C. Transcriptional regulation by p53. Cold Spring Harb Perspect Biol,2010,2:a00O935.
59. Strano S, Fontemaggi G, Costanzo A, Rizzo MG, Monti O,Baccarini A, Del Sal G, Levrero M, Sacchi A, Oren M, et al. Physical interaction with human tumorderived p53 mutants inhibits p63 activities. J Biol Chem,2002,277:18817-18826.
60. Di Agostino S, Strano S, Emiliozzi V, Zerbini V, Mottolese M, Sacchi A, Blandino G, Piaggio G. Gain of function of mutant p53:The mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell, 2006,10:191-202.
61. Yan W, Chen X. Identification of GRO1 as a critical determinant for mutant p53 gain of function. J Biol Chem,2009,284:12178-12187.
62. Yan W, Liu G, Scoumanne A, Chen X. Suppression of inhibitor of differentiation 2, a target of mutant p53, is required for gain-of-function mutations. Cancer Res,2008, 68:6789-6796.
63. Zalcenstein A, Weisz L, Stambolsky P, Bar J, Rotter V, Oren M. Repression of the MSP/MST-1 gene contributes to the antiapoptotic gain of function of mutant p53. Oncogen,2006,25:359-369.
64. Song H, Xu Y. Gain of function of p53 cancer mutants in disrupting critical DNA damage response pathways.Cell Cycle (Georgetown, Tex),2007,6:1570-1573.
65. Restle A, Farber M, Baumann C, Bohringer M, Scheidtmann KH, Muller-Tidow C,Wiesmuller L. Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants.Nucleic Acids Res, 2008,36:5362-5375.
66. Haupt S, di Agostino S, Mizrahi I, Alsheich-Bartok O, Voorhoeve M, Damalas A, Blandino G, Haupt Y. Promyelocytic leukemia protein is required for gain of function by mutant 53. Cancer Res,2009,69:4818-4826.
67. Terzian T, Suh YA, Iwakuma T, Post SM, Neumann M, Lang GA,Van Pelt CS, Lozano G. The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss.Genes Dev,2008,22:1337-1344.
68. Li Y, Guessous F, Kwon S, Kumar M, Ibidapo O, Fuller L, Johnson E, Lal B, Hussaini I, Bao Y, et al. PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations. Cancer Res,2008,68:1723-1731.
69. Lambert JM, Gorzov P, Veprintsev DB, Soderqvist M, Segerback D, Bergman J, Fersht AR, Hainaut P, Wiman KG, Bykov VJ. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell,2009,15:376-388.
2. Fang Chen, Wenge Wang, Wafik S. El-Deiry. Current strategies to target p53 in cancer. Bio Phar,2010,80:724-730.
3. Song H, Hollstein M, Xu Y. p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. Nat Cell Biol,2007,9:573-580.
4. Kalo E, Buganim Y, Shapira KE, Besserglick H, Goldfinger N, Weisz L, Stambolsky P, Henis YI, Rotter V. Mutant p53 attenuates the SMAD—dependent transforming growth factor beta I(TGF—beta I)signaling pathway by repressing the expression of TGF—beta receptor type II. Mol Cell Biol,2007,27:8228-8242.
5. A. Fire, S. Xu, M.K. Montgomery, S.A. Kostas, S.E. Driver, and C.C. Mello, Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature,1998,391(6669):806-11.
6. Ashihara E, Kawata E, Maekawa T. Future prospect of RNA interference for cancer therapies. Curr Drug Targets,2010,11(3):345360.
7. Merritt WM, Bar Eli M, Sood AK. The dicey role of Dicer:implications for RNAi therapy. Cancer Res,2010,70:2571-2574.
8. Phalon C, Rao DD, and Nemunaitis J, Potential use of RNA interference in cancer therapy. Expert Rev Mol Med,2010,12:e26.
9. Takeshita F and Ochiya T, Therapeutic potential of RNA interference against cancer. Cancer Sci,2006,97:689-96.
10. Heidenreich A, Aus G, Bolla M, Joniau S, Matveev VB, Schmid HP, and Zattoni F, EAU guidelines on prostate cancer. Eur Urol,2008,53(1):68-80.
11. Wolff JM, Chemotherapy in hormone-refractory prostate cancer. Front Radiat Ther Oncol,2008,41:103-7.
12. Bookstein R, MacGrogan D, Hilsenbeck SG, Sharkey F, and Allred DC, p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res,1993,53: 3369-73.
13. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics,2010. CA Cancer J Clin.2010 60(5):277-300.
14. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med.2003; 349:859-66.
15. Splinter TA, Scher HI, Denis L, et al. European Organization for Research on Treatment of Cancer-Genitourinary Group. The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. J Urol.1992; 147:606-8.
16. Vaughn DJ. Review and outlook for the role of paclitaxel in urothelial carcinoma. Semin Oncol.1999; 26:117-22.
1. Lane D and Levine A, p53 Research:the past thirty years and the next thirty years. Cold Spring Harb Perspect Biol,2010,2(12):a00O893.
2. Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, White R, and Vogelstein B, Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science,1989,244(4901):217-21.
3. Levine AJ, Momand J, and Finlay CA, The p53 tumour suppressor gene. Nature, 1991,351(6326):453-6.
4. Soussi T and Beroud C, Assessing Tp53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer,2001,1(3):233-40.
5. Goh AM, Coffill CR, and Lane DP, The role of mutant p53 in human cancer. J Pathol,2011,223(2):116-26.
6. Strano S, Dell'Orso S, Mongiovi AM, Monti O, Lapi E, Di Agostino S, Fontemaggi G, and Blandino G, Mutant p53 proteins:between loss and gain of function. Head Neck,2007,29(5):488-96.
7. Kastan MB and Berkovich E, p53:a two-faced cancer gene. Nat Cell Biol,2007, 9(5):489-91.
8. Oren M and Rotter V, Mutant p53 gain-of-function in cancer. Cold Spring Harb Perspect Biol,2010,2(2):a001107.
9. Navone NM, Troncoso P, Pisters LL, Goodrow TL, Palmer JL, Nichols WW, von Eschenbach AC, and Conti CJ, p53 protein accumulation and gene mutation in the progression of human prostate carcinoma. J Natl Cancer Inst,1993,85(20): 1657-69.
10. Perryman LA, Blair JM, Kingsley EA, Szymanska B, Ow KT, Wen VW, MacKenzie KL, Vermeulen PB, Jackson P, and Russell PJ, Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo. Biochem Biophys Res Commun,2006,345(3):1207-14.
11. Che M, DeSilvio M, Pollack A, Grignon DJ, Venkatesan VM, Hanks GE, and Sandier HM, Prognostic value of abnormal p53 expression in locally advanced prostate cancer treated with androgen deprivation and radiotherapy:a study based on RTOG 9202. Int J Radiat Oncol Biol Phys,2007,69(4):1117-23.
12. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, and Mello CC, Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature,1998,391(6669):806-11.
13. Rychahou PG, Jackson LN, Farrow BJ, and Evers BM, RNA interference: mechanisms of action and therapeutic consideration. Surgery,2006,140(5): 719-25.
14. Angaji SA, Hedayati SS, Poor RH, Madani S, Poor SS, and Panahi S, Application of RNA interference in treating human diseases. J Genet,2010, 89(4):527-37.
15. Phalon C, Rao DD, and Nemunaitis J, Potential use of RNA interference in cancer therapy. Expert Rev Mol Med,2010,12:e26.
16. Takeshita F and Ochiya T, Therapeutic potential of RNA interference against cancer. Cancer Sci,2006,97(8):689-96.
17. Efeyan A and Serrano M, p53:guardian of the genome and policeman of the oncogenes. Cell Cycle,2007,6(9):1006-10.
18. Heidenreich A, Aus G, Bolla M, Joniau S, Matveev VB, Schmid HP, and Zattoni F, EAU guidelines on prostate cancer. Eur Urol,2008,53(1):68-80.
19. Wolff JM, Chemotherapy in hormone-refractory prostate cancer. Front Radiat Ther Oncol,2008,41:103-7.
20. Takei Y, Kadomatsu K, Yuzawa Y, Matsuo S, and Muramatsu T, A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res,2004,64(10):3365-70.
21. Lee SO, Lou W, Qureshi KM, Mehraein-Ghomi F, Trump DL, and Gao AC, RNA interference targeting Stat3 inhibits growth and induces apoptosis of human prostate cancer cells. Prostate,2004,60(4):303-9.
22. De Schrijver E, Brusselmans K, Heyns W, Verhoeven G, and Swinnen JV, RNA interference-mediated silencing of the fatty acid synthase gene attenuates growth and induces morphological changes and apoptosis of LNCaP prostate cancer cells. Cancer Res,2003,63(13):3799-804.
23. Bullock AN and Fersht AR, Rescuing the function of mutant p53. Nat Rev Cancer,2001,1(1):68-76.
24. Maslon MM and Hupp TR, Drug discovery and mutant p53. Trends Cell Biol, 2010,20(9):542-55.
25. Ma LL, Sun WJ, Wang Z, Zh GY, Li P, and Fu SB, Effects of silencing of mutant p53 gene in human lung adenocarcinoma cell line Anip973. J Exp Clin Cancer Res,2006,25(4):585-92.
26. Sarker D, Reid AH, Yap TA, and de Bono JS, Targeting the PI3K/AKT pathway for the treatment of prostate cancer. Clin Cancer Res,2009,15(15):4799-805.
27. Yonesaka K, Tamura K, Kurata T, Satoh T, Ikeda M, Fukuoka M, and Nakagawa K, Small interfering RNA targeting survivin sensitizes lung cancer cell with mutant p53 to adriamycin. Int J Cancer,2006,118(4):812-20.
28. Niu J, Xu Z, Li XN, and Han Z, siRNA-mediated type 1 insulin-like growth factor receptor silencing induces chemosensitization of a human liver cancer cell line with mutant p53. Cell Biol Int,2007,31(2):156-64.
29. Bookstein R, MacGrogan D, Hilsenbeck SG, Sharkey F, and Allred DC, p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res,1993, 53(14):3369-73.
30. Downing S, Bumak C, Nixdorf S, Ow K, Russell P, and Jackson P, Elevated levels of prostate-specific antigen (PSA) in prostate cancer cells expressing mutant p53 is associated with tumor metastasis. Mol Carcinog,2003,38(3): 130-40.
31. Strano S, Dell'Orso S, Di Agostino S, Fontemaggi G, Sacchi A, and Blandino G, Mutant p53:an oncogenic transcription factor. Oncogene,2007,26(15):2212-9.
32. Li Y and Prives C, Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function? Oncogene,2007,26(15):2220-5.
33. Ghosh PM, Malik S, Bedolla R, and Kreisberg JI, Akt in prostate cancer: possible role in androgen-independence. Curr Drug Metab,2003,4(6):487-96.
34. Rege YD and Rangnekar VM, Molecular therapy intervention prospects in prostate cancer. Curr Pharm Des,2004,10(5):523-30.
35. Dong P, Xu Z, Jia N, Li D, and Feng Y, Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway. Mol Cancer, 2009,8:103.
36. Gesbert F, Sellers WR, Signoretti S, Loda M, and Griffin JD, BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27Kip1 through the phosphatidylinositol 3-Kinase/AKT pathway. J Biol Chem,2000,275(50): 39223-30.
37. Diehl JA, Cheng M, Roussel MF, and Sherr CJ, Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev,1998, 12(22):3499-511.
38. Boise LH, Gottschalk AR, Quintans J, and Thompson CB, Bcl-2 and Bcl-2-related proteins in apoptosis regulation. Curr Top Microbiol Immunol, 1995,200:107-21.
1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics,2010. CA Cancer J Clin.2010 60(5):277-300.
2. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med.2003; 349:859-66.
3. Splinter TA, Scher HI, Denis L, et al. European Organization for Research on Treatment of Cancer-Genitourinary Group. The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. J Urol.1992; 147:606-8.
4. Vaughn DJ. Review and outlook for the role of paclitaxel in urothelial carcinoma. Semin Oncol.1999; 26:117-22.
5. Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature 2009.458:1127-1130.
6. Vousden KH, Prives C. Blinded by the light:the growing complexity of p53. Cell 2009.137:413-431.
7. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991,253,49-53.
8. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000,408, 307-310.
9. Kato, S. et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc. Natl Acad. Sci. USA.2003,100,8424-9.
10. Milner J, Medcalf EA, Cook AC. Tumor suppressor p53:analysis of wild-type and mutant p53 complexes. Mol. Cell Biol.1991,11,12-19.
11. Milner J, Medcalf EA. Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation. Cell 1991,65,65-74.
12. Oren M, Rotter V. Mutant p53 Gain-of-Function in Cancer. Cold Spring Harb Perspect Biol 2010; 2:a001107.
13. Bossi, G. et al. Mutant p53 gain of function:reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene 2006,25,304-309.
14. Bossi, G. et al. Conditional RNA interference in vivo to study mutant p53 oncogenic gain of function on tumor malignancy. Cell Cycle.2008,7,1870-9.
15. Mitra AP, Datar RH, Cote RJ. Molecular pathways in invasive bladder cancer:New insights into mechanisms, progression, and target identification. J Clin Oncol.2006, 24:5552-5564. doi:10.1200/JCO.2006.08.2073.
16. Bakkar AA, Wallerand H, Radvanyi F, Lahaye JB, Pissard S, Lecerf L, Kouyoumdjian JC, Abbou CC, Pairon JC, Jaurand MC, Thiery JP, Chopin DK, de Medina SG. FGFR3 and Tp53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res.2003,63:8108-12.
17. Nishiyama H, Watanabe J, Ogawa O. p53 and chemosensitivity in bladder cancer. Int J Clin Oncol.2008,13:282-6.
18. Cooper MJ, Haluschak JJ, Johnson D, Schwartz S, Morrison LJ, Lippa M, Hatzivassiliou G and Tan J:p53 mutations in bladder carcinoma cell lines. Oncol Res,1994,6:569-579.
19. Riegerl KM, Little AF, Swart JM, Kastrinakis WV, Fitzgerald JM, Hess DT, Libertino JA, Summerhayes IC. Human bladder carcinoma cell lines as indicators of oncogenic change relevant to urothelial neoplastic progression. British Journal of Cancer.1995,72,683-690.
20. Weisz L, Oren M, Rotter V. Transcription regulation by mutant p53. Oncogene. 2007,26,2202-2211.
21. Donzelli, S. et al. Oncogenomic approaches in exploring gain of function of mutant p53. Curr. Genomics.2008,9,200-7.
22.张薇,项永兵,刘振伟,方茹蓉,阮志贤,孙璐,高立峰,金凡,高玉堂.1973-1999年上海市区老年人恶性肿瘤发病趋势分析.中华老年医学杂志,2005,24(9)：701-4.
23. Menendez D, Inga A, Resnick MA. The expanding universe of p53 targets. Nat Rev Cancer. Nat Rev Cancer.2009; 9(10):724-37.
24. Blandino G, Levine AJ, Oren M. Mutant p53 gain of function:differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene. 1999; 18:477-85.
25. Li R, Sutphin PD, Schwartz D, Matas D, Almog N, et al. Mutant p53 protein expression interferes with p53-independent apoptotic pathways. Oncogene.1998; 16: 3269-77.
26. Bergamaschi D, Gasco M, Hiller L, Sullivan A, Syed N, et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell.2003; 3:387-402.
27. Wolf D, Harris N, Rotter V. Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene. Cell.1984; 38:119-26.
28. Bumcrot D, Manoharan M, Koteliansky V, et al. RNAi therapeutics:a potential new class of pharmaceutical drugs. Nat. Chem. Biol.2006.2(12):711-9.
29. Castanotto D, Rossi JJ. The promises and pitfalls of RNA-interference-based therapeutics. Nature.2009,457(7228):426-33.
30. Ma LL, Sun WJ, Wang Z, Zh GY, Li P, et al. Effects of silencing of mutant p53 gene in human lung adenocarcinoma cell line Anip973. J Exp Clin Cancer Res.2006; 25: 585-92.
31. Zhu H, Mao Q, Lin Y, Yang K, Xie L. RNA interference targeting mutant p53 inhibits growth and induces apoptosis in DU145 human prostate cancer cells. Med Oncol.2010 Sep 21. [Epub ahead of print]
32. Hwang A, Muschell RJ. Radiation and the G2 phase of the cell cycle. Radiat. Res. 1998.150, S52-9.
33. Innocente SA, Abrahamson JLA, Cogswell JP, Lee JM. p53 regulates a G2 checkpoint through cyclin B1. Proc. Natl. Acad. Sci. USA.1999.96,2147-52.
34. Pagano M, Pepperkok R, Verde F, Ansorge W, Draetta G. Cyclin A is required at two points in the human cell cycle. EMBO. J.1992,11; 961-71.
35. Salvesen GS, Dixit VM. Caspase activation:the inducedproximity model. Proc Natl Acad Sci USA.1999; 96:10964-7.
36. Germain M, Affar EB, D'Amours D, et al. Cleavage of automodified poly (ADP-ribose) polymerase during apoptosis:evidence for involvement of caspase-7. J Biol Chem.1999; 274:28379-84.
37. Ivana Scovassi A, Diederich M. Modulation of poly (ADPribosylation) in apoptotic cells. Biochem Pharmacol.2004; 68:1041-7.
38. Lehmann J, Retz M, Stockle M. Chemotherapy in the post-MVAC era:the case for adjuvant chemotherapy. World J Urol.2002.20:144-50.
39. Ardavanis A, Tryfonopoulos D, Alexopoulos A, Kandylis C, Lainakis G, Rigatos G. Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase Ⅱ study. Br J Cancer.2005.92:645-50.
40. Rosenberg JE, Carroll PR, Small EJ. Update on chemotherapy for advanced bladder cancer. J Urology.2005.174:14-20.
41. Theodore C, Geoffrois L, Vermorken JB, Caponigro F, Fiedler W, Chollet P, et al. Multicentre EORTC study 16997:feasibility and phase Ⅱ trial of farnesyl transferase inhibitor & gemcitabine combination in salvage treatment of advanced urothelial tract cancers. Eur J Cancer.2005.41:1150-7.
42. Cote RJ, Esrig D, Groshen S, et al. p53 and treatment of bladder cancer. Nature. 1997,385:123-124
43. Watanabe J, Nishiyama H, Okubo K, et al. Clinical evaluation of p53 mutations in urothelial carcinoma by IHC and FASAY. Urology.2004,63:989-93.
44. Bergh J, Norberg T, Sjogren S, Lindgren A, Holmberg L. Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nature Med.1995,1, 1029-34.
45. Aas, T. et al. Specific p53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nature Med.1996,2,811-4.
46. Blandino G, Levine AJ, Oren M. Mutant p53 gain of function:differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene, 1999,18,477-85.
47. Lu C, El-Deiry WS. Targeting p53 for enhanced radio-and chemo-sensitivity. Apoptosis,2009,14,597-606.
48. Chin KV, Ueda K, Pastan I, Gottesman MM. Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. Science.1992,255,459-62.
49. Bush JA, Li G. Cancer chemoresistance:the relationship between p53 and multidrug transporters. Int. J. Cancer.2002,98,323-30.
50. Li R, et al. Mutant p53 protein expression interferes with p53-independent apoptotic pathways. Oncogene,1998,16,3269-77.
1. Rotter V. p53, a transformation-related cellularencoded protein, can be used as a biochemical marker for the detection of primary mouse tumor cells. Proc Natl Acad Sci,1983,80:2613-2617.
2. Michalovitz D, Halevy O, Oren M. p53 mutations:gains or losses? J Cell Bioch, 1991,45:22-29.
3. Sigal A, Rotter V. Oncogenic mutations of the p53 tumor suppressor:The demons of the guardian of the genome. Cancer Res,2000,60:6788-6793.
4. Weisz L, Oren M, Rotter V. Transcription regulation by mutant p53. Oncogene, 2007b,26:2202-2211.
5. Brosh R, Rotter V.2009. When mutants gain new powers:news from the mutant p53 field. Nature Rev Cancer,2009,9:701-13.
6. Donzelli S, Biagioni F, Fausti F, Strano S, Fontemaggi G,Blandino G. Oncogenomic Approaches in Exploring Gain of Function of Mutant p53. Current Genomics,2008, 9:200-207.
7. Lozano G. The oncogenic roles of p53 mutants in mouse models. Current opinion in genetics&development,2007,17:66-70.
8. Olivier M, Petitjean A, Marcel V, Petre A, Mounawar M,Plymoth A, de Fromentel CC, Hainaut P. Recent advances in p53 research:An interdisciplinary perspective.Cancer Gene Therapy,2009,16:1-12.
9. DittmerD, Pati S, Zambetti G, Chu S, Teresky AK,MooreM, Finlay C, Levine AJ. Gain of function mutations in p53. Nature Genetics,1993,4:42-46.
10. Levine AJ, Oren M. The first 30 years of p53:growing ever more complex. Nat Rev Cancer,2009,9:749-758.
11. Wolf D, Harris N, Rotter V. Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene. Cell,1984, 38:119-126.
12. Chin KV, Ueda K, Pastan I, Gottesman MM. Modulation of activity of the promoter of the humanMDR1gene by Ras and p53. Science,1992,255:459-462.
13. Deb S, Jackson CT, Subler MA, Martin DW. Modulation of cellular and viral promoters by mutant human p53 proteins found in tumor cells. J Virol,1992,66: 6164-6170.
14. Matas D, Sigal A, Stambolsky P, Milyavsky M, Weisz L, Schwartz D, Goldfinger N, Rotter V. Integrity of the N-terminal transcription domain of p53 is required for mutant p53 interference with drug-induced apoptosis. Embo J,2001,20: 4163-4172.
15. Gualberto A, Aldape K, Kozakiewicz K, Tlsty TD. An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Proc Natl Acad Sci USA,1998,95:5166-5171.
16. Iwamoto KS, Mizuno T, Ito T, Tsuyama N, Kyoizumi S, Seyama T. Gain-of-function p53 mutations enhance alteration of the T-cell receptor following X-irradiation, independently of the cell cycle and cell survival. Cancer Res,1996,56: 3862-3865.
17. Murphy KL, Dennis AP, Rosen JM. A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model. Faseb J,2000,14:2291-2302.
18. El-Hizawi S, Lagowski JP, Kulesz-Martin M, Albor A. Induction of gene amplification as a gain-of-function phenotype of mutant p53 proteins. Cancer Res, 2002,62:3264-3270.
19. Caulin C, Nguyen T, Lang GA, Goepfert TM, Brinkley BR, CaiWW, Lozano G, Roop DR. An inducible mouse model for skin cancer reveals distinct roles for gainand loss-of-function p53 mutations. J Clin Invest,2007,117:1893-1901.
20. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell,2005,7:469-483.
21.Talos F, Nemajerova A, Flores ER, Petrenko O, Moll UM. p73 suppresses polyploidy and aneuploidy in the absence of functional p53. Molecular Cell,2007, 27:647-659.
22. Offer H, Wolkowicz R, Matas D, Blumenstein S, Livneh Z, Rotter V. Direct involvement of p53 in the base excision repair pathway of the DNA repair machinery. FEBS Lett,1999,450:197-204.
23. Lotem J, Sachs L. Amutant p53 antagonizes the deregulated c-myc-mediated enhancement of apoptosis and decrease in leukemogenicity. Proc Natl Acad Sci USA,1995,92:9672-9676.
24. Peled A, Zipori D, Rotter V. Cooperation between p53-dependent and p53-independent apoptotic pathways in myeloid cells. Cancer Res,1996,56: 2148-2156.
25. Li R, Sutphin PD, Schwartz D, Matas D, Almog N, Wolkowicz R, Goldfinger N, Pei H, Prokocimer M, Rotter V. Mutant p53 protein expression interferes with p53-independent apoptotic pathways. Oncogene,1998,16:3269-3277.
26. Blandino G, Levine AJ, Oren M. Mutant p53 gain of function:differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene, 1999,18:477-485.
27. Yap DB, Hsieh JK, Zhong S, Heath V, Gusterson B, Crook T,Lu X. Ser392 phosphorylation regulates the oncogenic function of mutant p53. Cancer Res,2004, 64:4749-4754.
28. Vikhanskaya F, LeeMK, MazzolettiM, BrogginiM, Sabapathy K. Cancer-derived p53 mutants suppress p53-target gene expression-potential mechanism for gain of function of mutant p53. Nucleic Acids Res,2007,35:2093-2104.
29. Weisz L, Damalas A, Liontos M, Karakaidos P, Fontemaggi G, Maor-Aloni R, Kalis M, LevreroM, Strano S, Gorgoulis VG, et al. Mutant p53 enhances nuclear factor kappaB activation by tumor necrosis factor a in cancer cells. Cancer Res,2007a,67: 2396-2401.
30. Wong RP, Tsang WP, Chau PY, Co NN, Tsang TY, Kwok TT. p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3. Molecular Cancer Therapeutics,2007,6:1054-1061.
31. Bossi G, Lapi E, Strano S, Rinaldo C, Blandino G, Sacchi A. Mutant p53 gain of function:reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene,2006,25:304-309.
32. Olivier M, Hollstein M, Hainaut P. Tp53 mutations in human cancers:origins, consequences, and clinical use.Cold Spring Harb Perspect Biol,2010,2:a001008.
33. Vogelstein B, Kinzler KW. The multistep nature of cancer.Trends Genet,1993,9: 138-141.
34. Adorno M, Cordenonsi M,Montagner M, Dupont S,Wong C, Hann B, Solari A, Bobisse S, Rondina MB, Guzzardo V, et al. AMutant-p53/Smad complex opposes p63 to empower TGFb-induced metastasis. Cell,2009,137:87-98.
35. Wang SP, Wang WL, Chang YL, Wu CT, Chao YC, Kao SH,Yuan A, Lin CW, Yang SC, Chan WK, et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol,2009,11:694-704.
36. Buganim Y, Kalo E, Brosh R, Besserglick H, Nachmany I,Rais Y, Stambolsky P, Tang X, Milyavsky M, Shats I,et al. Mutant p53 protects cells from 12-Otetradecanoylphorbol-13-acetate-induced death by attenuating activating transcription factor 3 induction. Cancer Res,2006,66:10750-10759.
37. Dong P, Tada M, Hamada J, Nakamura A, Moriuchi T,Sakuragi N. p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells. Clin Exp Metastasis,2007,24:471-483.
38. Kalo E, Buganim Y, Shapira KE, Besserglick H, Goldfinger N, Weisz L, Stambolsky P, Henis YI, Rotter V. Mutant p53 attenuates the SMAD-dependent transforming growth factor b1 (TGF-b1) signaling pathway by repressing the expression of TGF-b receptor type II.Mol Cell Biol,2007,27:8228-8242.
39. Derynck R, Akhurst RJ, Balmain A. TGF-b signaling in tumor suppression and cancer progression. Nature Genetics,2001,29:117-129.
40. Massague J. TGF β in Cancer. Cell,2008,134:215-230.
41. Hsiao M, Low J, Dorn E, Ku D, Pattengale P, Yeargin J, Haas M. Gain-of-function mutations of the p53 gene induce lymphohematopoietic metastatic potential and tissue invasiveness. Am J Pathol,1994,145:702-14.
42. Lanyi A, Deb D, Seymour RC, Ludes-Meyers JH, Subler MA, Deb S.'Gain of function'phenotype of tumor-derived mutant p53 requires the oligomerization/nonsequence-specific nucleic acid-binding domain.Oncogene, 1998,16:3169-3176.
43. Duan W, Ding H, Subler MA, Zhu WG, Zhang H, Stoner GD, Windle JJ, Otterson GA, Villalona-Calero MA. Lung-specific expression of human mutant p53-273H is associated with a high frequency of lung adenocarcinoma in transgenic mice. Oncogene,2002,21:7831-7838.
44. Duan W, Gao L, Wu X, Hade EM, Gao JX, Ding H, Barsky SH, Otterson GA, Villalona-Calero MA. Expression of a mutant p53 results in an age-related demographic shift in spontaneous lung tumor formation in transgenic mice. PloS One,2009,4:e5563.
45. Heinlein C, Krepulat F, Lohler J, Speidel D, Deppert W.Tolstonog GV. Mutant p53 (R270H) gain of function phenotype in a mouse model for oncogeneinduced mammary carcinogenesis. Int J Cancer,2008,122:1701-1709.
46. Pohl J, Goldfinger N, Radler-Pohl A, Rotter V, Schirrmacher V. p53 increases experimental metastatic capacity of murine carcinoma cells. Mol Cell Biol,1988,8: 2078-2081.
47. Bossi G,Marampon F,Maor-Aloni R, Zani B, Rotter V, Oren M, Strano S, Blandino G, Sacchi A. Conditional RNA interference in vivo to study mutant p53 oncogenic gain of function on tumor malignancy. Cell Cycle (Georgetown, Tex),2008,7: 1870-1879.
48. Lang GA, Iwakuma T, Suh YA, Liu G, Rao VA, Parant JM, Valentin-Vega YA, Terzian T, Caldwell LC, Strong LC, et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell,2004,119:861-872.
49. Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, CrowleyD, Jacks T. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell, 2004,119:847-860.
50. Caulin C, Nguyen T, Lang GA, Goepfert TM, Brinkley BR,CaiWW, Lozano G, Roop DR. An inducible mouse model for skin cancer reveals distinct roles for gainand loss-of-function p53 mutations. J Clin Invest,2007,117:1893-1901.
51. Joerger AC, Fersht AR. Structural biology of the tumor suppressor p53. Annual review of biochemistry,2008,77:557-582.
52. Chin KV, Ueda K, Pastan I, Gottesman MM. Modulation of activity of the promoter of the humanMDR1gene by Ras and p53. Science,1992,255:459-462.
53. Frazier MW, He X, Wang J, Gu Z, Cleveland JL, Zambetti GP. Activation of c-myc gene expression by tumorderived p53 mutants requires a discrete C-terminal domain. Mol Cell Biol,1998,18:3735-3743.
54. Lee YI, Lee S, Das GC, Park US, Park SM, Lee YI. Activation of the insulin-like growth factor Ⅱ transcription by aflatoxin B1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma. Oncogene,2000,19:3717-3726.
55. Singer S, Ehemann V, Brauckhoff A, Keith M, Vreden S,Schirmacher P, Breuhahn K. Protumorigenic overexpression of stathmin/Opl8 by gain-of-function mutation in p53 in human hepatocarcinogenesis. Hepatology (Baltimore, Md),2007,46: 759-768.
56. Lavra L, Ulivieri A, Rinaldo C, Dominici R, Volante M, Luciani E, Bartolazzi A, Frasca F, Soddu S, Sciacchitano S. Gal-3 is stimulated by gain-of-function p53 mutations and modulates chemoresistance in anaplastic thyroid carcinomas. J Pathol, 2009,218:66-75.
57. Brosh R, Rotter V. When mutants gain new powers:news from the mutant p53 field. Nature Rev Cancer,2009,9:701-713.
58. Beckerman R, Prives C. Transcriptional regulation by p53. Cold Spring Harb Perspect Biol,2010,2:a00O935.
59. Strano S, Fontemaggi G, Costanzo A, Rizzo MG, Monti O,Baccarini A, Del Sal G, Levrero M, Sacchi A, Oren M, et al. Physical interaction with human tumorderived p53 mutants inhibits p63 activities. J Biol Chem,2002,277:18817-18826.
60. Di Agostino S, Strano S, Emiliozzi V, Zerbini V, Mottolese M, Sacchi A, Blandino G, Piaggio G. Gain of function of mutant p53:The mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell, 2006,10:191-202.
61. Yan W, Chen X. Identification of GRO1 as a critical determinant for mutant p53 gain of function. J Biol Chem,2009,284:12178-12187.
62. Yan W, Liu G, Scoumanne A, Chen X. Suppression of inhibitor of differentiation 2, a target of mutant p53, is required for gain-of-function mutations. Cancer Res,2008, 68:6789-6796.
63. Zalcenstein A, Weisz L, Stambolsky P, Bar J, Rotter V, Oren M. Repression of the MSP/MST-1 gene contributes to the antiapoptotic gain of function of mutant p53. Oncogen,2006,25:359-369.
64. Song H, Xu Y. Gain of function of p53 cancer mutants in disrupting critical DNA damage response pathways.Cell Cycle (Georgetown, Tex),2007,6:1570-1573.
65. Restle A, Farber M, Baumann C, Bohringer M, Scheidtmann KH, Muller-Tidow C,Wiesmuller L. Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants.Nucleic Acids Res, 2008,36:5362-5375.
66. Haupt S, di Agostino S, Mizrahi I, Alsheich-Bartok O, Voorhoeve M, Damalas A, Blandino G, Haupt Y. Promyelocytic leukemia protein is required for gain of function by mutant 53. Cancer Res,2009,69:4818-4826.
67. Terzian T, Suh YA, Iwakuma T, Post SM, Neumann M, Lang GA,Van Pelt CS, Lozano G. The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss.Genes Dev,2008,22:1337-1344.
68. Li Y, Guessous F, Kwon S, Kumar M, Ibidapo O, Fuller L, Johnson E, Lal B, Hussaini I, Bao Y, et al. PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations. Cancer Res,2008,68:1723-1731.
69. Lambert JM, Gorzov P, Veprintsev DB, Soderqvist M, Segerback D, Bergman J, Fersht AR, Hainaut P, Wiman KG, Bykov VJ. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell,2009,15:376-388.