口腔粘膜下纤维性变及其伴发口腔癌组织中MDM2及p21~（WAF/CIP1）的表达研究
|
摘要
目的:
研究口腔粘膜下纤维性变(oral submucous fibrosis,OSF)及其伴发口腔癌组织中MDM2、p21~(WAF/CIP1)蛋白的表达情况,探讨MDM2、p21~(WAF/CIP1)在OSF癌变机制中的作用。
方法:
选取经临床及病理确诊OSF患者44例,其中早期14例,中期15例,晚期15例,15例OSF伴发口腔癌组织,同时设置8例无口腔粘膜疾患、无烟、酒、槟榔等不良嗜好的健康志愿者的口腔粘膜相应组织为正常对照。免疫组化SP法检测上述各组MDM2、p21~(WAF/CIP1)蛋白的表达,并分析它们之间的相关性。
结果:
1.MDM2蛋白在正常口腔粘膜中阴性表达,在OSF及OSF伴发口腔癌组织中阳性表达。OSF中期、晚期组及OSF伴发口腔癌组显著高于正常对照组(P＜0.01);OSF伴发口腔癌组显著高于OSF各组(P＜0.01);OSF中期、晚期组显著高于OSF早期组(P＜0.01)。
2.p21~(WAF/CIP1)蛋白在正常口腔粘膜呈阳性表达,OSF组织及OSF伴发口腔癌组织中阳性表达逐渐减少。OSF组及OSF伴发口腔癌组中p21~(WAF/CIP1)阳性表达显著低于正常对照组(P＜0.01);OSF伴发口腔癌组与OSF早、中期组比较,阳性表达减少,差异有显著性(P＜0.01),与OSF晚期组比较,差异显著(P＜0.05)。
3.MDM2和p21~(WAF/CIP1)蛋白在OSF及OSF伴发口腔癌组织中的表达呈显著负相关,Pearson相关系数r=-0.763,P＜0.01。
结论:
1.OSF伴发口腔癌组织中MDM2蛋白阳性表达率明显高于OSF组织,推测过表达的MDM2蛋白可能通过促进p53蛋白经泛酸途径降解,野生型p53的抑癌活性丧失,导致肿瘤发生。
2.OSF伴发口腔癌组织中p21~(WAF/CIP1)蛋白阳性表达率明显低于OSF组织,推测p21~(WAF/CIP1)蛋白的减少失去对细胞增殖的抑制作用,导致肿瘤的发生。
3.MDM2、p21~(WAF/CIP1)蛋白在OSF及伴发口腔癌组织中的表达呈显著负相关,表明p21~(WAF/CIP1)可能受MDM2抑制作用,共同参与OSF的痛变。
Objective:
To investigate the expression of MDM2 and p21~(WAF/CIP1)protein in oral submucous fibrosis(OSF)and oral submucous fibrosis concomitant with oral squamous cell carcinoma(OSCC),and to evaluate their possible roles in carcinogenesis of OSF.
Method:
MDM2 and p21~(WAF/CIP1)protein expressions were assessed in 44 cases of OSF,15 cases of OSF concomitant with OSCC and 8 cases of normal control tissues via SP immunohistochemistry with the MDM2 and p21~(WAF/CIP1)rat anti-human monoclonal antibody.Statistic analysis was performed to figure out their expressions or correlation among their expressions and clinicopathological parameters of the patients with OSF concomitant with OSCC.
Results:
Positive MDM2-immunoreactivities were seen in early,middle,late stage OSF and OSF concomitant with OSCC,but negative in normal contol group.Positive p21~(WAF/CIP1)-immunoreactivities were seen in normal contol tissues and OSF,however.
The expression of MDM2 increased(P＜0.01),while the expression of p21~(WAF/CIP1)decreased(P＜0.01)in OSF concomitant with OSCC compared with those in normal control tissues.The expression of MDM2 in OSF concomitant with OSCC tissues was significantly higher than that in OSF and normal oral tissues(P＜0.01).The expression of MDM2 at middle and late stages increased when compared with early stage(P＜0.01). There was no significantly difference between middle and late stage of OSF.The expression of p21~(WAF/CIP1)in OSF concomitant with OSCC tissues was significantly lower than that in the early and middle stages of OSF tissues(P＜0.01).The expression of p21~(WAF/CIP1)in OSF concomitant with OSCC tissues was significantly lower than that in the late stage of OSF tissues(P＜0.05).There was a statistic inverse correlation between MDM2 and p21~(WAF/CIP1)expressions in OSF and OSF concomitant with OSCC tissues(r=-0.763,P＜0.01).
Conclusion:
The frequency of MDM2 protein positive expression in OSF concomitant with OSCC was obviously higher than thant in OSF tissues. It may act as an important role in carcinogenesis of OSF.The cyclin-dependent kinase inhibitor p21~(WAF/CIP1)protein positive expression was obviously lower in OSF concomitant with OSCC than in OSF.There was a statistic inverse correlation between MDM2 and p21~(WAF/CIP1) expressions in OSF and OSF concomitant with OSCC tissues.MDM2 could decrease the expression of p21~(WAF/CIP1)protein in OSF concomitant with OSCC.This study supports the hypothesis that they may contribute to the carcinogenesis of OSF.
研究口腔粘膜下纤维性变(oral submucous fibrosis,OSF)及其伴发口腔癌组织中MDM2、p21~(WAF/CIP1)蛋白的表达情况,探讨MDM2、p21~(WAF/CIP1)在OSF癌变机制中的作用。
方法:
选取经临床及病理确诊OSF患者44例,其中早期14例,中期15例,晚期15例,15例OSF伴发口腔癌组织,同时设置8例无口腔粘膜疾患、无烟、酒、槟榔等不良嗜好的健康志愿者的口腔粘膜相应组织为正常对照。免疫组化SP法检测上述各组MDM2、p21~(WAF/CIP1)蛋白的表达,并分析它们之间的相关性。
结果:
1.MDM2蛋白在正常口腔粘膜中阴性表达,在OSF及OSF伴发口腔癌组织中阳性表达。OSF中期、晚期组及OSF伴发口腔癌组显著高于正常对照组(P＜0.01);OSF伴发口腔癌组显著高于OSF各组(P＜0.01);OSF中期、晚期组显著高于OSF早期组(P＜0.01)。
2.p21~(WAF/CIP1)蛋白在正常口腔粘膜呈阳性表达,OSF组织及OSF伴发口腔癌组织中阳性表达逐渐减少。OSF组及OSF伴发口腔癌组中p21~(WAF/CIP1)阳性表达显著低于正常对照组(P＜0.01);OSF伴发口腔癌组与OSF早、中期组比较,阳性表达减少,差异有显著性(P＜0.01),与OSF晚期组比较,差异显著(P＜0.05)。
3.MDM2和p21~(WAF/CIP1)蛋白在OSF及OSF伴发口腔癌组织中的表达呈显著负相关,Pearson相关系数r=-0.763,P＜0.01。
结论:
1.OSF伴发口腔癌组织中MDM2蛋白阳性表达率明显高于OSF组织,推测过表达的MDM2蛋白可能通过促进p53蛋白经泛酸途径降解,野生型p53的抑癌活性丧失,导致肿瘤发生。
2.OSF伴发口腔癌组织中p21~(WAF/CIP1)蛋白阳性表达率明显低于OSF组织,推测p21~(WAF/CIP1)蛋白的减少失去对细胞增殖的抑制作用,导致肿瘤的发生。
3.MDM2、p21~(WAF/CIP1)蛋白在OSF及伴发口腔癌组织中的表达呈显著负相关,表明p21~(WAF/CIP1)可能受MDM2抑制作用,共同参与OSF的痛变。
Objective:
To investigate the expression of MDM2 and p21~(WAF/CIP1)protein in oral submucous fibrosis(OSF)and oral submucous fibrosis concomitant with oral squamous cell carcinoma(OSCC),and to evaluate their possible roles in carcinogenesis of OSF.
Method:
MDM2 and p21~(WAF/CIP1)protein expressions were assessed in 44 cases of OSF,15 cases of OSF concomitant with OSCC and 8 cases of normal control tissues via SP immunohistochemistry with the MDM2 and p21~(WAF/CIP1)rat anti-human monoclonal antibody.Statistic analysis was performed to figure out their expressions or correlation among their expressions and clinicopathological parameters of the patients with OSF concomitant with OSCC.
Results:
Positive MDM2-immunoreactivities were seen in early,middle,late stage OSF and OSF concomitant with OSCC,but negative in normal contol group.Positive p21~(WAF/CIP1)-immunoreactivities were seen in normal contol tissues and OSF,however.
The expression of MDM2 increased(P＜0.01),while the expression of p21~(WAF/CIP1)decreased(P＜0.01)in OSF concomitant with OSCC compared with those in normal control tissues.The expression of MDM2 in OSF concomitant with OSCC tissues was significantly higher than that in OSF and normal oral tissues(P＜0.01).The expression of MDM2 at middle and late stages increased when compared with early stage(P＜0.01). There was no significantly difference between middle and late stage of OSF.The expression of p21~(WAF/CIP1)in OSF concomitant with OSCC tissues was significantly lower than that in the early and middle stages of OSF tissues(P＜0.01).The expression of p21~(WAF/CIP1)in OSF concomitant with OSCC tissues was significantly lower than that in the late stage of OSF tissues(P＜0.05).There was a statistic inverse correlation between MDM2 and p21~(WAF/CIP1)expressions in OSF and OSF concomitant with OSCC tissues(r=-0.763,P＜0.01).
Conclusion:
The frequency of MDM2 protein positive expression in OSF concomitant with OSCC was obviously higher than thant in OSF tissues. It may act as an important role in carcinogenesis of OSF.The cyclin-dependent kinase inhibitor p21~(WAF/CIP1)protein positive expression was obviously lower in OSF concomitant with OSCC than in OSF.There was a statistic inverse correlation between MDM2 and p21~(WAF/CIP1) expressions in OSF and OSF concomitant with OSCC tissues.MDM2 could decrease the expression of p21~(WAF/CIP1)protein in OSF concomitant with OSCC.This study supports the hypothesis that they may contribute to the carcinogenesis of OSF.
引文
[1]Pindborg JJ,Murtip R.Oral Submucous Fibrosis as a precancerous condition[J].Stand J Dent Res,1984,92(3):224-229.
[2]Murti PR,Bhonsle RB,Pindborg J J,et al.Malignant transformation rate in oral submucous fibrosis over a 17-year period[J].Community Dent Oral Epidemiol,1985,13(6):340-341.
[3]高义军,凌天牖,尹晓敏.口腔粘膜下纤维性变癌变的回顾性研究[J].临床口腔医学杂志,2005,21(2):119-120.
[4]Hsue SS,Wang WC,Chen CH,et al.Malignant transformation in 1458 patients with potentially malignant oral mucosal disorders:a follow-up study based in a Taiwanese hospital[J].J Oral Pathol Med,2007,36(1):25-29.
[5]Control of oral cancer in developing countries.A WHO meeting[R].Bull World Health Organ,1984,62:817-830.
[6]World Health Organization,International Agency for Research on Cancer.Betel Quid and Areca-Nut Chewing.IARC Monographs on the Evaluation of Carcinogenic Risks to Humans[R].Lyon:International Agency for Research on Cancer,1985,37:137-202.
[7]Murthi PR,Bhonsle RB,Gupta PC,et al.Etiology of Oral submucous fibrosis with special references to the role of areca nut chewing[J].J Oral Pathol Med,1995,24:145-152.
[8]Gupta PC,Warnakulasuriya S.Global Epidemiology of areca nut usage[J].Addict Biol,2002,7:77-83.
[9]Gunaseelan R,Shanthi S,Sowmya R,Datta M.Areca nut use among rural reside- nts of Sriperambudur Taluk:A qualitative study[J].Indian J Dent Res,2007,18:11-4.
[10]Gupta PC,Ray CS.Epidemiology of betel quid usage[J].Ann Acad Med Singapore,2004,33:31-36.
[11]Jyotsna Changrani,Francesca M.Gany,Gustavo Cruz et al.Paan and Gutka Use in the United States: A Pilot Study in Bangladeshi and Indian Gujarati Immigrants in New York City[J]. J Immigr Rerag Stud, 2006,4(1): 99-110.
[12] V.K.Hazarey, D.M.Erlewad, K.A.Mundhe, et al. Oral submucous fibrosis: study of 1000 cases from central India[J]. Journal of Oral Pathology & Medicine, 2007,36(1): 12-17.
[13] Che-Chun Su, Hsiu-Fei Yang, Shu-Ju Huang, et al. Distinctive Features of Oral Cancer in Changhua County: High Incidence, Buccal Mucosa Preponderance,and a Close Relation to Betel Quid Chewing Habit[J]. J Formos Med Assoc,2007,106(3): 225-233.
[14] Guimaraes DP, Hainaut P. TP53: a key gene in human cancer[J]. Biochimie,2002, 84:83-93.
[15] Xiao ZX, Chen J, Levine AJ, et al. Interaction between the retinobl -astoma protein and the oncoprotein in MDM2[J]. Nature, 1995, 375 (6533) : 694-698.
[16] Momand J, Zambetti CP, Oson DC , et al. The Mdm2 oncogene product forms a complex with the p53 protein and inhibits p53 mediated transactiv- ation[J].Cell, 1992,69:1237-1245.
[17] Haupt S, Louria-Hayon I, Haupt Y. P53 licensed to kill? Operating the assassin[J]. J Cell Biochem, 2003, 88: 76-82.
[18] Miwa S, Uchida C, Kitagawa K, et al. Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner[J].Biochem Biophys Res Commun, 2006, 340(1): 54-61.
[19] El-Deiry W, Harper JW, O'Connor PM, et al.WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis[J]. Cancer Res, 1994, 54: 1169-1174.
[20] Harper, J. W., Adami, G R., Wei, N., et al. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of Gl cyclin-dependent kinases[J]. Cell, 1993, 75: 805-816.
[21] El-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression[J]. Cell, 1993, 75: 817-825.
[22] Zehbe I, Ratsch A, Alunni-Fabbroni M, et al. Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions[J]. Oncogene, 1999, 18(13): 2201-11.
[23]刘节,陈素兰,张伟等.食管癌P21WAF1表达与P53突变的关系[J].世界华人消化杂志,2000,8(12):1350-1353.
[24]Wamakulasuriya S,Trivedy C,Peters TJ.Areca nut use:An independent risk factor for oral cancer[J].BMJ,2002,324:799-800.
[25]Jon Sudbo.Novel Management of Oral Cancer:A Paradigm of Predictive Oncology[J].Clin Med Res,2004,2(4):233-242.
[26]Ferlay J,Bray F,Pisani P,et al.Globocan 2000,Cancer Incidence,Mortality and Prevalence Worldwide.Version 1.0.Lyon[R],France:IARC Press,2001.
[27]Lo WL,Kao SY,Chi LY,et al.Outcomes of oral squamous cell carcinoma in Taiwan after surgical therapy:factors affecting survival[J].J Oral Maxillofac Surg,2003,61:751-758.
[28]Brinkman BM,Wong DT.Disease mechanism and biomarkers of oral squamous cell carcinoma[J].Curr Opin Oncol,2006,18(3):228-233.
[29]Myoung H,Kim M J,Lee JH,et al.Correlation of proliferative markers(Ki-67and PCNA)with survival and lymph node metastasis in oral squamous cell carcinoma:a clinical and histopathological analysis of 113 patients[J],hat J Oral Maxillofac Surg,2006,35(11):1005-1010.
[30]高义军,凌天牖,尹晓敏等.口腔粘膜下纤维性变及其癌变组织中端粒酶逆转录酶的表达[J].实用口腔医学杂志,2006,22(3):302-304.
[31]Loro LL,Johannessen AC,Vintermyr OK.Decreased expression of bcl-2 in moderate and severe oral epithelia dysplasias[J].Oral Oncol,2002,38(7):691-8.
[32]Scheper MA,Nikitakis NG,Sauk JJ.Survivin is a downstream target and effector of sulindac-sensitive oncogenic Stat3 signalling in head and neck cancer[J].Int J Oral Maxillofac Surg,2007,36(7):632-639.
[33]Chiang CP,Lang MJ,Liu BY,et al.Expression of proliferating cell nuclear antigen(PCNA)in oral submucous fibrosis,oral epithelial hyperkeratosis and oral epithelial dysplasia in Taiwan[J].Oral Oncol,2000,36:353-9.
[34]Yamamoto N,Kuroiwa T,Katakura A,et al.Loss of heterozygosity(LOH)on chromosomes 2q,3p and 21q in Indian oral squamous cell carcinoma[J].Bull Tokyo Dent Coll,2007,48(3):109-117.
[35]Poh CF,Zhang L,Anderson DW,et al,Fluorescence visualization detection of field alterations in tumor margins of oral cancer patients[J].Clin Cancer Res,2006,12(22):6716-6722.
[36]Sonia Ayll6n Barbellido,Julian Campo Trapero,Jorge Cano Sanchez,et al.Gene therapy in the management of oral cancer:Review of the literature[J].Med Oral Patol Oral Cir Bucal,2008,13(1):E15-E21.
[37]李海如,郑健,袁苏娟.口腔粘膜鳞癌和癌前病变p53、ras基因突变的检测及p53、p21蛋白的表达[J].口腔颌面外科杂志,2000,10(2):131-133.
[38]Chiang CP,Lang MJ,Liu BY,et al.Expression of p53 protein in oral submucous fibrosis,oral epithelial hyperkeratosis,and oral epithelial dysplasia[J].J Formos Med Assoc,2000,99(3):229-34.
[39]Liao PH,Lee TL,Yang LC,et al.Adenomatous polyposis coli gene mutation and decreased wild-type p53 protein expression in oral submucous fibrosis:a preliminary investigation[J].Oral Surg Oral Med Oral Pathol Oral Radiol Endod,2001,92(2):202-7.
[40]Pfeifer GP,Denissenko MF,et al.Tobacco smoke carcinogens,DNA damage and p53 mutations in smoking-associated cancers[J].Oncogene,2002,21:7435-7451.
[41]Helene Blons 1,Pierre Laurent-Puig.TP53 and head and neck neoplasms[J].Human Mutation,2003,(21):252-257.
[42]Ogrnundsd6ttir HM,Hilmarsdottir H,Astvaldsd6ttir A,et al.Oral lichen planus has a high rate of TP53 mutations.A study of oral mucosa in icelanD[J].Eur J Oral Sci,2002,110(3):192-8.
[43]Shahnavaz SA,Regezi JA,Bradley G,et al.p53 gene mutations in sequential oral epithelial dysplasias and squamous cell carcinomas[J].J Pathol,2000,190(4):417-22.
[44]Ferbeyre G,de Stanchina E,Lin AW,et al.Oncogenic ras and p53 cooperate to induce cellular senescence[J].Mol Cell Biol,2002,22(10):3497-3508.
[45]LevinA,MomandJ,FinlayC.The p53 tumor suppressor gene[J].Nature,1991,351(6326):453-456
[46] Oliner JD, Kinzler KW, Meltzer PS, et al. Amplification of a gene encoding a p53 associated protein in human sarcomas[J]. Nature, 1992, 358 (6381): 80-83.
[47] Bond GL, Hu W, Levine AJ. MDM2 is a central node in the p53 pathway: 12 years and counting[J]. Curr Cancer Drug Targets, 2005, 5: 3-8.
[48] Peng Y, Chen L, Li, et al. Stabilization of the MDM2 oncoprotein by mutant p53[J]. J Biol Chem, 2001, 276(9): 6874-6878.
[49] Shinozaki T, Nota A, Taya Y, Okamoto K.Functional role of Mdm2 phosphoryl-ation by ATR in attenuation of p53 nuclear export[J]. Oncogene, 2003, 22(55):8870- 80.
[50] Maya R, Balass M, Kim ST, et al. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage[J].Genes Dev, 2001,15(9):1067- 77.
[51] Liggett WH Jr, Sewell DA, Rocco J, et al. pl6 and p16beta are potent growth suppressors of head and neck squamous carcinoma cell in vitro[J]. Cancer Res,1996,56:4119-4123.
[52] Arap W, Knudsen E, Sewell DA, et al. Functional analysis of wild-type and malignant glioma derived CDKN2Abeta alleles: Evidence for an RB-independent growth suppressive pathway[J]. Oncogene, 1997,15: 2013-20.
[53] Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2[J]. Science, 2004, 303: 844-848.
[54] Freedman DA, Wu L , Levine AJ. Functions of the MDM2 oncoprotein[J]. Cell Mol Life Sci, 1999,55:96-107.
[55] Mathew R,Arora S, Khanna R, et al. Alterations in p53 and pRb pat- hways and their prognostic significance in oesophageal cancer[J]. Eur J Cancer, 2002, 38(6): 832-841.
[56] Huang JS, Ho TJ, Chiang CP, et al. MDM2 expression in areca quid chewing-associated oral squamous cell carcinomas in Taiwan[J]. J Oral Pathol Med, 2001,30(1):53-8.
[57] Ranju Ralhan, Agarwal Sandhya, Mathur Meera, et al. Induction of MDM2-P2 Transcripts Correlates with Stabilized Wild-Type p53 in Betel- and Tobacco-Related Human Oral Cancer[J]. American Journal of Pathology, 2000,157: 587-596.
[58] HauptY, Maya R, Kazaz A, et al. MDM2 promotes the rapid Degradation of p53[J].Nature, 1997, 387(6630): 296-299.
[59] Schmitt CA, Fridman JS, Yang M, et al.Dissecting p53 tumor suppressor Functions in vivo[J]. Cancer Cell, 2002,1(3): 335-346.
[60] Ghosh A, Stewart D, Matlashewski G. Regulation of human p53 activity and cell localization by alternative splicing[J]. Mol Cell Biol, 2004, 24: 7987-7997.
[61] Weissman AM. The mess and variations on ubiquitylation. Nat Rev Mol Cell Biol, 2001,2(3): 169-178.
[62] Lain S, Lane D. Improving cancer therapy by non-genotoxic activation of p53[J].Eur J Cancer, 2003, 39: 1053-1060.
[63] Chen PC, Kuo C, Pan CC, et al. Risk of oral cancer associated with human papillomavirus infection,betel quid chewing and cigarette smoking in Taiwan an integrated molecular and epidemiological study of 58 cases[J]. J Oral Pathol Med.2002, 31(6): 317.
[64] Deng C, Zhang P, Harper JW, et al. Mice lacking p21~(CIP1/WAF1) undergo normal development, but are defective in G1 checkpoint control[J]. Cell, 1995, 82:675-684.
[65] Barboza JA, Liu G,Ju Z, et al. p21 delays tumor onset by preservation of chromosomal stability[J]. Proc Natl Acad Sci U S A, 2006, 103(52): 19842-7.
[66] Kudo Y, Takata T, Ogawa I, et al. Expression of p53 and p21~(CIP1/WAF1) proteins in oral epithelial dysplasias and squamous cell carcinomas[J]. Oncol Rep,1999,6:539-545.
[67] Deeds L, Teodorescu S, Chu M,et al. A p53-independent Gl cell cycle checkpoint induced by the suppression of protein kinase C alpha and theta isoforms[J]. J Biol Chem, 2003,278: 39782-39793
[68] Wafik S. El-Deiry, Takashi Tokino,Todd Waldman, et al. Topological control of p21~(WAF1/CIPE1) eXpression in normal and neoplastic tissues[J]. Cancer Research,1995,55:2910-2919.
[69]Aksam J.Merched,Lawrence Chan.Absence of p21Waf1/Cip1/Sdi1 Modulates Macrophage Differentiation and Inflammatory Response and Protects Against Athero-sclerosis[J].Circulation,2004,110:3830-3841.
[70]Berghrnans S,Murphey RD,Wienholds E,et al.tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors[J].Proc Natl Acad Sci U S A,2005,102(2):407-412.
[71]Yook JI,Kim J.Expression of p21~(WAF1/CIPI)is unrelated to p53 tumor suppre- ssor gene status in oral squamous cell carcinoma[J].Oral Oncol,1998,34:198-203.
[72]蔡扬,何园,卢虹等.口腔鳞状细胞癌cyclin E及p21waf1蛋白定量检测及意义[J].中国肿瘤临,2008,35(3):142-144.
[73]何国斌,姜育红,赵红宇等.口腔鳞状细胞癌发生发展过程中P21wafl表达的研究[J].口腔医学,2000,20(2):66-67.
[74]Sheaff R.J.,Singer,J.D.,Swanger,J.,et al.Proteasomal turnover of p21Cip1does not require p21Cip1 ubiquitination[J].Mol.Cell,2000,5:403-410.
[75]Jin Y,Lee H,Zeng SX,et al.MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation[J].EMBO J,2003,22(23):6365-77.
[1]Vogelstein B,Lane D,Levine AJ:Surfing the p53 network[J].Nature 2000,408(6810):307-310.
[2]Giaccia AJ,Kastan MB.The complexity of p53 modulation:emerging patterns from divergent signals[J].Genes Dev 1998,12(19):2973-2983.
[3]Gaumont-Leclerc MF,Mukhopadhyay UK,Goumard S,et al.PEA-15 is inhibited by adenovirns E1A and plays a role in ERK nuclear export and Ras-induced senescence[J].J Biol Chem 2004,279(45):46802-46809.
[4]Ferbeyre G,de Stanchina E,Querido E,et al.PML is induced by oncogenic ras and promotes premature senescence[J].Genes Dev,2000,14(16):2015-2027.
[5]Ferbeyre G,de Stanchina E,Lin AW,Querido E,McCurrach ME,Hannon GJ,Lowe SW:Oncogenic ras and p53 cooperate to induce cellular senescence[J].Mol Cell Biol,2002,22(10):3497-3508.
[6]Balint E E,Vousden K H.Activation and activities of the p53 tumor suppressor protein[J].Br J Cancer,2001,85:1813-1823.
[7]Foster BA,Coffey HA,Morin MJ,et al.Pharmacological rescue of mutant p53conformation and function[J].Science,1999,286(5449):2507-10.
[8]Kerr,JF,Wyllie,AH,Currie,AR.Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics[J].Br J Cancer,1972,26:239-257.
[9]Huang,DC,Strasser,A.BH3-Only proteins-essential initiators of apoptotic cell death[J]. Cell, 2000,103: 839-842.
[10] Shats I, Milyavsky M, Tang X, et al. p53 dependent down regulation of telomerase is mediated by p21waf1[J]. J Biol Chem, 2004,279(49): 50976-85.
[11] Lane D. Anthony dipple carcinogenesis award. P53 from pathway to therapy[J].Carcinogenesis, 2004,25:1077-1081.
[12] Jiang Y, Saavedra HI, Holloway MP, et al. Aberrant regulation of survivin by the RB/E2F family of proteins[J]. J Biol Chem, 2004, 279(39): 40511-20.
[13] Rogoff HA, Kowalik TF. Life, death and E2F: linking proliferation control and DNA damage signaling via E2Fl[J].Cell Cycle, 2004, 3(7): 845-6.
[14] Stark G R, Taylor W R. Analyzing the G2/M checkpoint[J]. Methods Mol Biol,2004,280:51-82.
[15] Lawlor ER, Soucek L, Brown-Swigart L, et al. Reversible kinetic analysis of Myc targets in vivo provides novel insights into Myc-mediated tumorigenesis[J].Cancer Res, 2006, 66(9): 4591-601.
[16] Laane E, Panaretakis T, Pokrovskaja K, et al. Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members[J]. Haematologica, 2007, 92(11): 1460-9.
[17] Fan J, Li R, Zhang R, Liu HL, et al. Effect of Bcl-2 and Bax on survival of side population cells from hepatocellular carcinoma cells[J]. World J Gastroenterol.2007, 13(45): 6053-9.
[18] Cerutti E, Campagnoli MF, Ferretti M, et al. Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome[J].BMC Immunol, 2007, 8: 28.
[19] Haince JF, Kozlov S, Dawson VL, et al. Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents[J]. J Biol Chem, 2007,282 (22): 16441-53.
[20] Dai MS, Lu H. Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5[J]. J Biol Chem, 2004, 279(43): 44475-82.
[21] Dai MS, Zeng SX, Jin Y, et al. Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition[J]. Mol Cell Biol, 2004, 24(17): 7654-68.
[22] Uchida C, Miwa S, Kitagawa K, et al. Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation[J]. EMBO J, 2005,24(1): 160-169.
[23] Miwa S, Uchida C, Kitagawa K, et al. Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner[J]. Biochem Biophys Res Commun, 2006, 340(1): 54-61.
[24] Oliner JD, Kinzler KW, Meltzer PS, et al. Amplification of a gene encoding a p53-associated protein in human sarcomas[J]. Nature, 1992, 358: 80-83.
[25] Alarconvargas D, Ronai Z. p53/MDM2 the affair that never ends[J]. Carcinoge- nesis, 2002,23(4): 541-547.
[26] Secchiero P, Corallini F, Gonelli A, et al. Antiangiogenic Activity of the MDM2 Antagonist Nutlin-3[J]. Circ Res, 2007, 100(1): 61-69.
[27] Paola Secchiero, Carlotta Zerbinati, Elisabetta Melloni, et al. The MDM2 Antagonist Nutlin-3 Promotes the Maturation of Acute Myeloid Leukemic[J].Neoplasia,2007,9(10): 853-861.
[28]顾军,尹大力.抗肿瘤药物研制的新靶点MDM2-P53[J］ 药学进展, 2003,27(1): 15.
[29] Chene P, Fuchs J, Bohn J, et al. A small synthetic peptide, which inhibits the p53 MDM2 interaction, stimulates the p53 pathway in tumour cell[J]. J Mol Biol,2000, 299: 245-253
[30] Duan WL, Gao LJ, Druhan, et al. Villalona-Calero. Expression of Pirh2, a newly identified ubiquitin protein ligase, in lung cancer[J]. J Natl. Cancer Inst, 2004,96: 1718-1721.
[31] Logan IR, V Sapountzi, L Gaughan, et al. Control of human PIRH2 protein stability: involvement of TIP60 and the proteosome[J]. J Biol Chem, 2004, 279:11696-11704.
[32] Wu TT, Wang JS, Jiaan BP, et al. Role of p21(WAFl) and p27(KIPl) in predicting biochemical recurrence for organ-confined prostate adenocarcinoma[J]. J Chin Med Assoc, 2007, 70(1): 11-15.
[33] Dulic V, Kaufmann W, Wilsan J, et al. p53-dependent inhibitor of cyclin-dependent Kinase activities in human fibroblasts during radiation induced G1 arrest[J]. Cell, 1994, 76:1013.
[34] Waldman J, Kinzler W, Vogelsdtein B, et al. p21WAFl is necessary for the p53-mediated G1 arrest in human cancer cells[J]. Cancer Res, 1995, 55: 5187.
[35] Marchetti A, Doglioni C, Barbaroschi M, et al. The p21 RNA and protein expression in non-small cell lung carcinomas showing evidence of p53 independent expression and association with tumor differentiation[J]. Oncogene,1996,12:1319-1320.
[36] Jiang H. Lin J, Su ZZ, et al. The melanona differentiation associated gene mda-6,Which encodes the cyclin|dependent kinase inhibitor p21 is differentiatedly expressed during growth, differentiation and progression in human melanoma cells[J]. Oncogene, 1995, 10(9): 1855-1864.
[37] Honda R, Yasuda H. Association of pl9(ARF) with Mdm2 inhibits ubiquitin ligase activity of mdm2 for tumor suppressor p53[J]. EMBO J, 1999, 18(1):22-27.
[38] Tao W, Levine AJ. p19(ARF)stabilizes p53 by blocking nucleo-cytoplasmic shuttling of mdm2[J]. Proc Natl Acad Sci USA, 1999, (12): 6937-41.
[39] Bertwistle D, Sherr CJ Regulation of the Arf tumor suppressor in Emicro-Myc transgenic mice: longitudinal study of Myc-induced lymphomagenesis[J]. Blood,2007,109(2): 792-794.
[40] den Besten W, Kuo ML, Williams RT, Sherr CJ. Myeloid leukemia-associated nucleophosmin mutants perturb p53-dependent and independent activities of the Arf tumor suppressor protein[J]. Cell Cycle, 2005, 4(11): 1593-8.
[41] Cheng, E. H.-Y. A. et al. BCL-2, BCL-XL sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis[J]. Mol.Cell, 2001, 8: 705-711.
[42] Chandra D, Choy G, Daniel PT, Tang DG. Bax-dependent regulation of Bak by voltage-dependent anion channel 2[J]. J Biol Chem, 2005, 280(19): 19051-61.
[43] Shimazu T, Degenhardt K, Nur-E-Kamal A, et al. NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibition[J]. Genes Dev, 2007, 21(8): 929-41.
[44] Shibue T, Suzuki S, Okamoto H, et al. Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways[J]. EMBO J, 2006,25(20): 4952- 62.
[45] Erlacher M, Michalak EM, Kelly PN, et al. BH3-only proteins Puma and Bimare rate-limiting for gamma-radiation and glucocorticoid-induced apoptosis of lymphoid cells in vivo[J]. Blood, 2005, 106(13): 4131-8.
[46] Aoudjit F, Vuori K. Matrix attachment regulates Fas-induced apoptosis in endoth- elial cells: a role for c-flip and implications for anoikis[J]. J CellBiol,2001,152:633-643.
[47] Shao RG, Cao CX, Nieves-Neira W, et al. Activation of the Fas pathway independently of Fas ligand during apoptosis induced by camptothecin in p53 mutant human colon carcinoma cells[J].Oncogene, 2001, 20: 1852-1859.
[48] Agami R, Bernards R. Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage[J]. Cell,2000, 102: 55-66.
[49] Marin MC, Jost CA, Irwin MS, et al. Viral oncoproteins discriminate between p53 and the p53 homolog p73[J]. Mol Cell Biol, 1998,18: 6316-6324.
[50] Jost CA, Marin MC, Kaelin WG Jr. p73 is a simian [correction of human] p53-related protein that can induce apoptosis[J]. Nature, 1997, 389: 191-194.
[51] Gaiddon C, Lokshin M, Gross I, et al. Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73[J]. J Biol Chem, 2003, 278: 27421-31.
[52] Kang MJ, Park BJ, Byun DS, et al. Loss of imprinting and elevated expression of wild-type p73 in human gastric adenocarcinoma[J]. Clin Cancer Res, 2000, 6:1767-1771.
[53] Takahashi H, Fukutome K, Watanabe M, et al. Mutation analysis of the p51 gene and correlation between p53, p73, and p51 expressions in prostatic carcinoma[J].Prostate;2001,47: 85-90.
[54] Shinozaki H, Okamoto A, Shimizu K, et al. Absence of p51 alteration in human ovarian cancer[J]. Int J Oncol, 2001,18: 549-552.
[2]Murti PR,Bhonsle RB,Pindborg J J,et al.Malignant transformation rate in oral submucous fibrosis over a 17-year period[J].Community Dent Oral Epidemiol,1985,13(6):340-341.
[3]高义军,凌天牖,尹晓敏.口腔粘膜下纤维性变癌变的回顾性研究[J].临床口腔医学杂志,2005,21(2):119-120.
[4]Hsue SS,Wang WC,Chen CH,et al.Malignant transformation in 1458 patients with potentially malignant oral mucosal disorders:a follow-up study based in a Taiwanese hospital[J].J Oral Pathol Med,2007,36(1):25-29.
[5]Control of oral cancer in developing countries.A WHO meeting[R].Bull World Health Organ,1984,62:817-830.
[6]World Health Organization,International Agency for Research on Cancer.Betel Quid and Areca-Nut Chewing.IARC Monographs on the Evaluation of Carcinogenic Risks to Humans[R].Lyon:International Agency for Research on Cancer,1985,37:137-202.
[7]Murthi PR,Bhonsle RB,Gupta PC,et al.Etiology of Oral submucous fibrosis with special references to the role of areca nut chewing[J].J Oral Pathol Med,1995,24:145-152.
[8]Gupta PC,Warnakulasuriya S.Global Epidemiology of areca nut usage[J].Addict Biol,2002,7:77-83.
[9]Gunaseelan R,Shanthi S,Sowmya R,Datta M.Areca nut use among rural reside- nts of Sriperambudur Taluk:A qualitative study[J].Indian J Dent Res,2007,18:11-4.
[10]Gupta PC,Ray CS.Epidemiology of betel quid usage[J].Ann Acad Med Singapore,2004,33:31-36.
[11]Jyotsna Changrani,Francesca M.Gany,Gustavo Cruz et al.Paan and Gutka Use in the United States: A Pilot Study in Bangladeshi and Indian Gujarati Immigrants in New York City[J]. J Immigr Rerag Stud, 2006,4(1): 99-110.
[12] V.K.Hazarey, D.M.Erlewad, K.A.Mundhe, et al. Oral submucous fibrosis: study of 1000 cases from central India[J]. Journal of Oral Pathology & Medicine, 2007,36(1): 12-17.
[13] Che-Chun Su, Hsiu-Fei Yang, Shu-Ju Huang, et al. Distinctive Features of Oral Cancer in Changhua County: High Incidence, Buccal Mucosa Preponderance,and a Close Relation to Betel Quid Chewing Habit[J]. J Formos Med Assoc,2007,106(3): 225-233.
[14] Guimaraes DP, Hainaut P. TP53: a key gene in human cancer[J]. Biochimie,2002, 84:83-93.
[15] Xiao ZX, Chen J, Levine AJ, et al. Interaction between the retinobl -astoma protein and the oncoprotein in MDM2[J]. Nature, 1995, 375 (6533) : 694-698.
[16] Momand J, Zambetti CP, Oson DC , et al. The Mdm2 oncogene product forms a complex with the p53 protein and inhibits p53 mediated transactiv- ation[J].Cell, 1992,69:1237-1245.
[17] Haupt S, Louria-Hayon I, Haupt Y. P53 licensed to kill? Operating the assassin[J]. J Cell Biochem, 2003, 88: 76-82.
[18] Miwa S, Uchida C, Kitagawa K, et al. Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner[J].Biochem Biophys Res Commun, 2006, 340(1): 54-61.
[19] El-Deiry W, Harper JW, O'Connor PM, et al.WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis[J]. Cancer Res, 1994, 54: 1169-1174.
[20] Harper, J. W., Adami, G R., Wei, N., et al. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of Gl cyclin-dependent kinases[J]. Cell, 1993, 75: 805-816.
[21] El-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression[J]. Cell, 1993, 75: 817-825.
[22] Zehbe I, Ratsch A, Alunni-Fabbroni M, et al. Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions[J]. Oncogene, 1999, 18(13): 2201-11.
[23]刘节,陈素兰,张伟等.食管癌P21WAF1表达与P53突变的关系[J].世界华人消化杂志,2000,8(12):1350-1353.
[24]Wamakulasuriya S,Trivedy C,Peters TJ.Areca nut use:An independent risk factor for oral cancer[J].BMJ,2002,324:799-800.
[25]Jon Sudbo.Novel Management of Oral Cancer:A Paradigm of Predictive Oncology[J].Clin Med Res,2004,2(4):233-242.
[26]Ferlay J,Bray F,Pisani P,et al.Globocan 2000,Cancer Incidence,Mortality and Prevalence Worldwide.Version 1.0.Lyon[R],France:IARC Press,2001.
[27]Lo WL,Kao SY,Chi LY,et al.Outcomes of oral squamous cell carcinoma in Taiwan after surgical therapy:factors affecting survival[J].J Oral Maxillofac Surg,2003,61:751-758.
[28]Brinkman BM,Wong DT.Disease mechanism and biomarkers of oral squamous cell carcinoma[J].Curr Opin Oncol,2006,18(3):228-233.
[29]Myoung H,Kim M J,Lee JH,et al.Correlation of proliferative markers(Ki-67and PCNA)with survival and lymph node metastasis in oral squamous cell carcinoma:a clinical and histopathological analysis of 113 patients[J],hat J Oral Maxillofac Surg,2006,35(11):1005-1010.
[30]高义军,凌天牖,尹晓敏等.口腔粘膜下纤维性变及其癌变组织中端粒酶逆转录酶的表达[J].实用口腔医学杂志,2006,22(3):302-304.
[31]Loro LL,Johannessen AC,Vintermyr OK.Decreased expression of bcl-2 in moderate and severe oral epithelia dysplasias[J].Oral Oncol,2002,38(7):691-8.
[32]Scheper MA,Nikitakis NG,Sauk JJ.Survivin is a downstream target and effector of sulindac-sensitive oncogenic Stat3 signalling in head and neck cancer[J].Int J Oral Maxillofac Surg,2007,36(7):632-639.
[33]Chiang CP,Lang MJ,Liu BY,et al.Expression of proliferating cell nuclear antigen(PCNA)in oral submucous fibrosis,oral epithelial hyperkeratosis and oral epithelial dysplasia in Taiwan[J].Oral Oncol,2000,36:353-9.
[34]Yamamoto N,Kuroiwa T,Katakura A,et al.Loss of heterozygosity(LOH)on chromosomes 2q,3p and 21q in Indian oral squamous cell carcinoma[J].Bull Tokyo Dent Coll,2007,48(3):109-117.
[35]Poh CF,Zhang L,Anderson DW,et al,Fluorescence visualization detection of field alterations in tumor margins of oral cancer patients[J].Clin Cancer Res,2006,12(22):6716-6722.
[36]Sonia Ayll6n Barbellido,Julian Campo Trapero,Jorge Cano Sanchez,et al.Gene therapy in the management of oral cancer:Review of the literature[J].Med Oral Patol Oral Cir Bucal,2008,13(1):E15-E21.
[37]李海如,郑健,袁苏娟.口腔粘膜鳞癌和癌前病变p53、ras基因突变的检测及p53、p21蛋白的表达[J].口腔颌面外科杂志,2000,10(2):131-133.
[38]Chiang CP,Lang MJ,Liu BY,et al.Expression of p53 protein in oral submucous fibrosis,oral epithelial hyperkeratosis,and oral epithelial dysplasia[J].J Formos Med Assoc,2000,99(3):229-34.
[39]Liao PH,Lee TL,Yang LC,et al.Adenomatous polyposis coli gene mutation and decreased wild-type p53 protein expression in oral submucous fibrosis:a preliminary investigation[J].Oral Surg Oral Med Oral Pathol Oral Radiol Endod,2001,92(2):202-7.
[40]Pfeifer GP,Denissenko MF,et al.Tobacco smoke carcinogens,DNA damage and p53 mutations in smoking-associated cancers[J].Oncogene,2002,21:7435-7451.
[41]Helene Blons 1,Pierre Laurent-Puig.TP53 and head and neck neoplasms[J].Human Mutation,2003,(21):252-257.
[42]Ogrnundsd6ttir HM,Hilmarsdottir H,Astvaldsd6ttir A,et al.Oral lichen planus has a high rate of TP53 mutations.A study of oral mucosa in icelanD[J].Eur J Oral Sci,2002,110(3):192-8.
[43]Shahnavaz SA,Regezi JA,Bradley G,et al.p53 gene mutations in sequential oral epithelial dysplasias and squamous cell carcinomas[J].J Pathol,2000,190(4):417-22.
[44]Ferbeyre G,de Stanchina E,Lin AW,et al.Oncogenic ras and p53 cooperate to induce cellular senescence[J].Mol Cell Biol,2002,22(10):3497-3508.
[45]LevinA,MomandJ,FinlayC.The p53 tumor suppressor gene[J].Nature,1991,351(6326):453-456
[46] Oliner JD, Kinzler KW, Meltzer PS, et al. Amplification of a gene encoding a p53 associated protein in human sarcomas[J]. Nature, 1992, 358 (6381): 80-83.
[47] Bond GL, Hu W, Levine AJ. MDM2 is a central node in the p53 pathway: 12 years and counting[J]. Curr Cancer Drug Targets, 2005, 5: 3-8.
[48] Peng Y, Chen L, Li, et al. Stabilization of the MDM2 oncoprotein by mutant p53[J]. J Biol Chem, 2001, 276(9): 6874-6878.
[49] Shinozaki T, Nota A, Taya Y, Okamoto K.Functional role of Mdm2 phosphoryl-ation by ATR in attenuation of p53 nuclear export[J]. Oncogene, 2003, 22(55):8870- 80.
[50] Maya R, Balass M, Kim ST, et al. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage[J].Genes Dev, 2001,15(9):1067- 77.
[51] Liggett WH Jr, Sewell DA, Rocco J, et al. pl6 and p16beta are potent growth suppressors of head and neck squamous carcinoma cell in vitro[J]. Cancer Res,1996,56:4119-4123.
[52] Arap W, Knudsen E, Sewell DA, et al. Functional analysis of wild-type and malignant glioma derived CDKN2Abeta alleles: Evidence for an RB-independent growth suppressive pathway[J]. Oncogene, 1997,15: 2013-20.
[53] Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2[J]. Science, 2004, 303: 844-848.
[54] Freedman DA, Wu L , Levine AJ. Functions of the MDM2 oncoprotein[J]. Cell Mol Life Sci, 1999,55:96-107.
[55] Mathew R,Arora S, Khanna R, et al. Alterations in p53 and pRb pat- hways and their prognostic significance in oesophageal cancer[J]. Eur J Cancer, 2002, 38(6): 832-841.
[56] Huang JS, Ho TJ, Chiang CP, et al. MDM2 expression in areca quid chewing-associated oral squamous cell carcinomas in Taiwan[J]. J Oral Pathol Med, 2001,30(1):53-8.
[57] Ranju Ralhan, Agarwal Sandhya, Mathur Meera, et al. Induction of MDM2-P2 Transcripts Correlates with Stabilized Wild-Type p53 in Betel- and Tobacco-Related Human Oral Cancer[J]. American Journal of Pathology, 2000,157: 587-596.
[58] HauptY, Maya R, Kazaz A, et al. MDM2 promotes the rapid Degradation of p53[J].Nature, 1997, 387(6630): 296-299.
[59] Schmitt CA, Fridman JS, Yang M, et al.Dissecting p53 tumor suppressor Functions in vivo[J]. Cancer Cell, 2002,1(3): 335-346.
[60] Ghosh A, Stewart D, Matlashewski G. Regulation of human p53 activity and cell localization by alternative splicing[J]. Mol Cell Biol, 2004, 24: 7987-7997.
[61] Weissman AM. The mess and variations on ubiquitylation. Nat Rev Mol Cell Biol, 2001,2(3): 169-178.
[62] Lain S, Lane D. Improving cancer therapy by non-genotoxic activation of p53[J].Eur J Cancer, 2003, 39: 1053-1060.
[63] Chen PC, Kuo C, Pan CC, et al. Risk of oral cancer associated with human papillomavirus infection,betel quid chewing and cigarette smoking in Taiwan an integrated molecular and epidemiological study of 58 cases[J]. J Oral Pathol Med.2002, 31(6): 317.
[64] Deng C, Zhang P, Harper JW, et al. Mice lacking p21~(CIP1/WAF1) undergo normal development, but are defective in G1 checkpoint control[J]. Cell, 1995, 82:675-684.
[65] Barboza JA, Liu G,Ju Z, et al. p21 delays tumor onset by preservation of chromosomal stability[J]. Proc Natl Acad Sci U S A, 2006, 103(52): 19842-7.
[66] Kudo Y, Takata T, Ogawa I, et al. Expression of p53 and p21~(CIP1/WAF1) proteins in oral epithelial dysplasias and squamous cell carcinomas[J]. Oncol Rep,1999,6:539-545.
[67] Deeds L, Teodorescu S, Chu M,et al. A p53-independent Gl cell cycle checkpoint induced by the suppression of protein kinase C alpha and theta isoforms[J]. J Biol Chem, 2003,278: 39782-39793
[68] Wafik S. El-Deiry, Takashi Tokino,Todd Waldman, et al. Topological control of p21~(WAF1/CIPE1) eXpression in normal and neoplastic tissues[J]. Cancer Research,1995,55:2910-2919.
[69]Aksam J.Merched,Lawrence Chan.Absence of p21Waf1/Cip1/Sdi1 Modulates Macrophage Differentiation and Inflammatory Response and Protects Against Athero-sclerosis[J].Circulation,2004,110:3830-3841.
[70]Berghrnans S,Murphey RD,Wienholds E,et al.tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors[J].Proc Natl Acad Sci U S A,2005,102(2):407-412.
[71]Yook JI,Kim J.Expression of p21~(WAF1/CIPI)is unrelated to p53 tumor suppre- ssor gene status in oral squamous cell carcinoma[J].Oral Oncol,1998,34:198-203.
[72]蔡扬,何园,卢虹等.口腔鳞状细胞癌cyclin E及p21waf1蛋白定量检测及意义[J].中国肿瘤临,2008,35(3):142-144.
[73]何国斌,姜育红,赵红宇等.口腔鳞状细胞癌发生发展过程中P21wafl表达的研究[J].口腔医学,2000,20(2):66-67.
[74]Sheaff R.J.,Singer,J.D.,Swanger,J.,et al.Proteasomal turnover of p21Cip1does not require p21Cip1 ubiquitination[J].Mol.Cell,2000,5:403-410.
[75]Jin Y,Lee H,Zeng SX,et al.MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation[J].EMBO J,2003,22(23):6365-77.
[1]Vogelstein B,Lane D,Levine AJ:Surfing the p53 network[J].Nature 2000,408(6810):307-310.
[2]Giaccia AJ,Kastan MB.The complexity of p53 modulation:emerging patterns from divergent signals[J].Genes Dev 1998,12(19):2973-2983.
[3]Gaumont-Leclerc MF,Mukhopadhyay UK,Goumard S,et al.PEA-15 is inhibited by adenovirns E1A and plays a role in ERK nuclear export and Ras-induced senescence[J].J Biol Chem 2004,279(45):46802-46809.
[4]Ferbeyre G,de Stanchina E,Querido E,et al.PML is induced by oncogenic ras and promotes premature senescence[J].Genes Dev,2000,14(16):2015-2027.
[5]Ferbeyre G,de Stanchina E,Lin AW,Querido E,McCurrach ME,Hannon GJ,Lowe SW:Oncogenic ras and p53 cooperate to induce cellular senescence[J].Mol Cell Biol,2002,22(10):3497-3508.
[6]Balint E E,Vousden K H.Activation and activities of the p53 tumor suppressor protein[J].Br J Cancer,2001,85:1813-1823.
[7]Foster BA,Coffey HA,Morin MJ,et al.Pharmacological rescue of mutant p53conformation and function[J].Science,1999,286(5449):2507-10.
[8]Kerr,JF,Wyllie,AH,Currie,AR.Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics[J].Br J Cancer,1972,26:239-257.
[9]Huang,DC,Strasser,A.BH3-Only proteins-essential initiators of apoptotic cell death[J]. Cell, 2000,103: 839-842.
[10] Shats I, Milyavsky M, Tang X, et al. p53 dependent down regulation of telomerase is mediated by p21waf1[J]. J Biol Chem, 2004,279(49): 50976-85.
[11] Lane D. Anthony dipple carcinogenesis award. P53 from pathway to therapy[J].Carcinogenesis, 2004,25:1077-1081.
[12] Jiang Y, Saavedra HI, Holloway MP, et al. Aberrant regulation of survivin by the RB/E2F family of proteins[J]. J Biol Chem, 2004, 279(39): 40511-20.
[13] Rogoff HA, Kowalik TF. Life, death and E2F: linking proliferation control and DNA damage signaling via E2Fl[J].Cell Cycle, 2004, 3(7): 845-6.
[14] Stark G R, Taylor W R. Analyzing the G2/M checkpoint[J]. Methods Mol Biol,2004,280:51-82.
[15] Lawlor ER, Soucek L, Brown-Swigart L, et al. Reversible kinetic analysis of Myc targets in vivo provides novel insights into Myc-mediated tumorigenesis[J].Cancer Res, 2006, 66(9): 4591-601.
[16] Laane E, Panaretakis T, Pokrovskaja K, et al. Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members[J]. Haematologica, 2007, 92(11): 1460-9.
[17] Fan J, Li R, Zhang R, Liu HL, et al. Effect of Bcl-2 and Bax on survival of side population cells from hepatocellular carcinoma cells[J]. World J Gastroenterol.2007, 13(45): 6053-9.
[18] Cerutti E, Campagnoli MF, Ferretti M, et al. Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome[J].BMC Immunol, 2007, 8: 28.
[19] Haince JF, Kozlov S, Dawson VL, et al. Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents[J]. J Biol Chem, 2007,282 (22): 16441-53.
[20] Dai MS, Lu H. Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5[J]. J Biol Chem, 2004, 279(43): 44475-82.
[21] Dai MS, Zeng SX, Jin Y, et al. Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition[J]. Mol Cell Biol, 2004, 24(17): 7654-68.
[22] Uchida C, Miwa S, Kitagawa K, et al. Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation[J]. EMBO J, 2005,24(1): 160-169.
[23] Miwa S, Uchida C, Kitagawa K, et al. Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner[J]. Biochem Biophys Res Commun, 2006, 340(1): 54-61.
[24] Oliner JD, Kinzler KW, Meltzer PS, et al. Amplification of a gene encoding a p53-associated protein in human sarcomas[J]. Nature, 1992, 358: 80-83.
[25] Alarconvargas D, Ronai Z. p53/MDM2 the affair that never ends[J]. Carcinoge- nesis, 2002,23(4): 541-547.
[26] Secchiero P, Corallini F, Gonelli A, et al. Antiangiogenic Activity of the MDM2 Antagonist Nutlin-3[J]. Circ Res, 2007, 100(1): 61-69.
[27] Paola Secchiero, Carlotta Zerbinati, Elisabetta Melloni, et al. The MDM2 Antagonist Nutlin-3 Promotes the Maturation of Acute Myeloid Leukemic[J].Neoplasia,2007,9(10): 853-861.
[28]顾军,尹大力.抗肿瘤药物研制的新靶点MDM2-P53[J］ 药学进展, 2003,27(1): 15.
[29] Chene P, Fuchs J, Bohn J, et al. A small synthetic peptide, which inhibits the p53 MDM2 interaction, stimulates the p53 pathway in tumour cell[J]. J Mol Biol,2000, 299: 245-253
[30] Duan WL, Gao LJ, Druhan, et al. Villalona-Calero. Expression of Pirh2, a newly identified ubiquitin protein ligase, in lung cancer[J]. J Natl. Cancer Inst, 2004,96: 1718-1721.
[31] Logan IR, V Sapountzi, L Gaughan, et al. Control of human PIRH2 protein stability: involvement of TIP60 and the proteosome[J]. J Biol Chem, 2004, 279:11696-11704.
[32] Wu TT, Wang JS, Jiaan BP, et al. Role of p21(WAFl) and p27(KIPl) in predicting biochemical recurrence for organ-confined prostate adenocarcinoma[J]. J Chin Med Assoc, 2007, 70(1): 11-15.
[33] Dulic V, Kaufmann W, Wilsan J, et al. p53-dependent inhibitor of cyclin-dependent Kinase activities in human fibroblasts during radiation induced G1 arrest[J]. Cell, 1994, 76:1013.
[34] Waldman J, Kinzler W, Vogelsdtein B, et al. p21WAFl is necessary for the p53-mediated G1 arrest in human cancer cells[J]. Cancer Res, 1995, 55: 5187.
[35] Marchetti A, Doglioni C, Barbaroschi M, et al. The p21 RNA and protein expression in non-small cell lung carcinomas showing evidence of p53 independent expression and association with tumor differentiation[J]. Oncogene,1996,12:1319-1320.
[36] Jiang H. Lin J, Su ZZ, et al. The melanona differentiation associated gene mda-6,Which encodes the cyclin|dependent kinase inhibitor p21 is differentiatedly expressed during growth, differentiation and progression in human melanoma cells[J]. Oncogene, 1995, 10(9): 1855-1864.
[37] Honda R, Yasuda H. Association of pl9(ARF) with Mdm2 inhibits ubiquitin ligase activity of mdm2 for tumor suppressor p53[J]. EMBO J, 1999, 18(1):22-27.
[38] Tao W, Levine AJ. p19(ARF)stabilizes p53 by blocking nucleo-cytoplasmic shuttling of mdm2[J]. Proc Natl Acad Sci USA, 1999, (12): 6937-41.
[39] Bertwistle D, Sherr CJ Regulation of the Arf tumor suppressor in Emicro-Myc transgenic mice: longitudinal study of Myc-induced lymphomagenesis[J]. Blood,2007,109(2): 792-794.
[40] den Besten W, Kuo ML, Williams RT, Sherr CJ. Myeloid leukemia-associated nucleophosmin mutants perturb p53-dependent and independent activities of the Arf tumor suppressor protein[J]. Cell Cycle, 2005, 4(11): 1593-8.
[41] Cheng, E. H.-Y. A. et al. BCL-2, BCL-XL sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis[J]. Mol.Cell, 2001, 8: 705-711.
[42] Chandra D, Choy G, Daniel PT, Tang DG. Bax-dependent regulation of Bak by voltage-dependent anion channel 2[J]. J Biol Chem, 2005, 280(19): 19051-61.
[43] Shimazu T, Degenhardt K, Nur-E-Kamal A, et al. NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibition[J]. Genes Dev, 2007, 21(8): 929-41.
[44] Shibue T, Suzuki S, Okamoto H, et al. Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways[J]. EMBO J, 2006,25(20): 4952- 62.
[45] Erlacher M, Michalak EM, Kelly PN, et al. BH3-only proteins Puma and Bimare rate-limiting for gamma-radiation and glucocorticoid-induced apoptosis of lymphoid cells in vivo[J]. Blood, 2005, 106(13): 4131-8.
[46] Aoudjit F, Vuori K. Matrix attachment regulates Fas-induced apoptosis in endoth- elial cells: a role for c-flip and implications for anoikis[J]. J CellBiol,2001,152:633-643.
[47] Shao RG, Cao CX, Nieves-Neira W, et al. Activation of the Fas pathway independently of Fas ligand during apoptosis induced by camptothecin in p53 mutant human colon carcinoma cells[J].Oncogene, 2001, 20: 1852-1859.
[48] Agami R, Bernards R. Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage[J]. Cell,2000, 102: 55-66.
[49] Marin MC, Jost CA, Irwin MS, et al. Viral oncoproteins discriminate between p53 and the p53 homolog p73[J]. Mol Cell Biol, 1998,18: 6316-6324.
[50] Jost CA, Marin MC, Kaelin WG Jr. p73 is a simian [correction of human] p53-related protein that can induce apoptosis[J]. Nature, 1997, 389: 191-194.
[51] Gaiddon C, Lokshin M, Gross I, et al. Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73[J]. J Biol Chem, 2003, 278: 27421-31.
[52] Kang MJ, Park BJ, Byun DS, et al. Loss of imprinting and elevated expression of wild-type p73 in human gastric adenocarcinoma[J]. Clin Cancer Res, 2000, 6:1767-1771.
[53] Takahashi H, Fukutome K, Watanabe M, et al. Mutation analysis of the p51 gene and correlation between p53, p73, and p51 expressions in prostatic carcinoma[J].Prostate;2001,47: 85-90.
[54] Shinozaki H, Okamoto A, Shimizu K, et al. Absence of p51 alteration in human ovarian cancer[J]. Int J Oncol, 2001,18: 549-552.