Role of MDM2 in Cell Proliferation and Tumorigenesis

MDM2 在细胞增殖和肿瘤发生中的作用

• 批准号: 7816712
• 负责人: ZHI-XIONG Jim XIAO
• 金额: $ 27.77万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7816712
• 关键词: Acidic Region; Alleles; Amino Acids; Binding; Biological; Cell Cycle Arrest; Cell Proliferation; Cultured Cells; Cyclin D1; Cyclin E; Data; Development; Drug Delivery Systems; Etiology; Funding; Gene Mutation; Homologous Gene; Human; Lymphomagenesis; MDM2 gene; Malignant Neoplasms; Mediating; Molecular; Mutation; Oncogene Proteins; Oncogenic; Pathway interactions; Phase; Phosphorylation; Phosphotransferases; Play; Principal Investigator; Procedures; Regulation; Retinoblastoma Protein; Role; Serine; Signal Transduction; TP53 gene; Therapeutic; Transgenic Mice; Tumor Suppressor Proteins; Viral; Work; base; cancer prevention; carcinogenesis; cell growth; in vivo; insight; kinase inhibitor; mouse model; multicatalytic endopeptidase complex; overexpression; programs; protein degradation; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The broad objective of this proposal for continuation of R01CA79804 is to elucidate the role of MDM2 on cell proliferation and tumorigenesis. MDM2 has p53-dependent and p53-independent oncogenic functions. While MDM2 p53-dependent function has been intensively studied, the p53-independent functions of MDM2 are not well understood. This application focuses on MDM2-mediated regulation on retinoblastoma protein (Rb). Work from us and others showed that MDM2 interacts with Rb and promotes S-phase entry independent of p53. We recently showed that MDM2 binds to the Rb C-pocket and disrupts Rb-E2F interaction. Furthermore, we demonstrated that activation of MDM2 promotes Rb protein degradation in a proteasome-dependent pathway whereas knockdown of MDM2 results in accumulation of Rb and cell cycle arrest. In this continuation application, we hypothesize that MDM2-mediated Rb destabilization critically contributes to pathological progress of tumorigenesis. Specific Aim 1 is to elucidate the molecular mechanism by which MDM2 regulates Rb. Specific Aim 2 is to investigate the roles of MDMx and tumor suppressor protein ARF in modulation of MDM2-Rb and Specific aim 3 is to examine the role of MDM2-Rb in tumorigenesis in vivo. Information obtained from this study will provide considerable insight of the biological and pathological role of MDM-Rb in cell proliferation and human tumorigenesis. Inactivation of retinoblastoma protein (Rb) is critical in human cancer development. Rb can be inactivated by gene mutations and by abnormal hyperphosphorylation. How Rb is degraded is poorly understood. Work from us and others demonstrates that the cellular oncoprotein MDM2 also targets and promotes Rb protein degradation. This study is aimed at elucidating the role of he MDM2-Rb pathway in human tumorigenesis. Information obtained from this study would further our understanding of human carcinogenesis and help identify therapeutic drug targets for cancer prevention and treatment.

描述（由申请人提供）：该提案的延续R01CA79804的广泛目标是阐明MDM2在细胞增殖和肿瘤发生中的作用。 MDM2具有p53依赖性和p53独立的致癌功能。尽管已深入研究了MDM2 p53依赖性函数，但MDM2的p53独立函数尚不清楚。该应用集中于MDM2介导的视网膜细胞瘤蛋白（RB）的调节。我们和其他人的工作表明，MDM2与RB相互作用，并促进独立于p53的S相进入。我们最近表明，MDM2与RB C口袋结合并破坏RB-E2F相互作用。此外，我们证明MDM2的激活促进了蛋白酶体依赖性途径中的RB蛋白降解，而MDM2的敲低导致RB的积累和细胞周期停滞。在此连续应用中，我们假设MDM2介导的RB不稳定促进了肿瘤发生的病理进步。具体目的1是阐明MDM2调节RB的分子机制。具体目的2是研究MDMX和肿瘤抑制蛋白ARF在MDM2-RB调节中的作用，而特定目标3是检查MDM2-RB在体内肿瘤发生中的作用。从这项研究中获得的信息将为MDM-RB在细胞增殖和人类肿瘤发生中的生物学和病理作用提供大量见解。 视网膜细胞瘤蛋白（RB）的失活在人类癌症发展中至关重要。 RB可以被基因突变和异常的高磷酸化灭活。 RB如何降解的理解很少。我们和其他人的工作表明，细胞癌蛋白MDM2还靶向并促进RB蛋白降解。这项研究旨在阐明HE MDM2-RB途径在人类肿瘤发生中的作用。从这项研究中获得的信息将进一步了解人类癌变，并有助于确定用于预防癌症和治疗的治疗药物靶标。

项目成果

TAp63 is a transcriptional target of NF-kappaB.

• DOI: 10.1002/jcb.22449
• 发表时间: 2010-03-01
• 期刊: JOURNAL OF CELLULAR BIOCHEMISTRY
• 影响因子: 4
• 作者: Wu, Junfeng;Bergholz, Johann;Lu, Jinin;Sonenshein, Gail E.;Xiao, Zhi-Xiong Jim
• 通讯作者: Xiao, Zhi-Xiong Jim

Rapamycin inhibits IGF-1-mediated up-regulation of MDM2 and sensitizes cancer cells to chemotherapy.

• DOI: 10.1371/journal.pone.0063179
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Du W;Yi Y;Zhang H;Bergholz J;Wu J;Ying H;Zhang Y;Xiao ZX
• 通讯作者: Xiao ZX

Pin1 inhibits PP2A-mediated Rb dephosphorylation in regulation of cell cycle and S-phase DNA damage.

Pin1 抑制 PP2A 介导的 Rb 去磷酸化，从而调节细胞周期和 S 期 DNA 损伤。

• DOI: 10.1038/cddis.2015.3
• 发表时间: 2015-02-12
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Tong Y;Ying H;Liu R;Li L;Bergholz J;Xiao ZX
• 通讯作者: Xiao ZX