Regulation of Cellular Senescence and Oncogenic Transformation by Sin3B.

Sin3B 对细胞衰老和致癌转化的调节。

• 批准号: 8761315
• 负责人: Gregory David
• 金额: $ 28.31万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-16 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761315
• 关键词: Acceleration; Aging; Biochemical; Biological; Bypass; Cancerous; Cell Aging; Cell Cycle; Cells; Chromatin; Complex; Cultured Cells; Cyclin-Dependent Kinase Inhibitor; Data; Event; Exhibits; Family; Fibroblasts; G1/S Transition; Gene Targeting; Genes; Genetic; Genetically Engineered Mouse; Goals; Health; Histone Deacetylase; Histones; Human; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mammals; Mediating; Molecular; Mutation; Oncogene Activation; Oncogenes; Oncogenic; PTEN gene; Pathway interactions; Phenotype; Prevention; Prostate; Prostatic Neoplasms; Proteins; Regulation; Research; Role; Signal Transduction; Staging; Stress; Testing; Therapeutic Intervention; Transcription Repressor/Corepressor; Tumor Suppression; Tumor Suppressor Proteins; Up-Regulation; Withdrawal; base; cancer initiation; driving force; gene repression; in vivo; metaplastic cell transformation; mouse model; overexpression; prevent; programs; promoter; research study; senescence; tumor; tumor progression

DESCRIPTION (provided by applicant): Cellular senescence, a permanent cell cycle exit triggered by different stresses, has recently emerged as a safeguard mechanism against both uncontrolled proliferation and the accumulation of deleterious genetic alterations that occur during oncogenic transformation. Markers of cellular senescence have been identified in early stage human cancers, including preneoplastic prostate lesions, but are lost as the tumors progress. Consistent with a role of senescence in the prevention of tumor progression, genetic inactivation of essential components of the senescence pathway in mouse models leads to the acceleration of cancer progression. Despite accumulating evidence for its biological relevance in tumor suppression, the molecular bases underlying the establishment of cellular senescence remain largely elusive. Recently, the transcriptional silencing of pro-proliferative genes via heterochromatinization has been shown to correlate with the permanent senescence-associated cell cycle exit. Our preliminary results using genetically engineered mice and cells, demonstrate that the histone deacetylase (HDAC) associated Sin3B protein is required for both replicative and oncogene-induced cellular senescence. In addition, Sin3B is specifically induced upon oncogenic stress, and its overexpression is sufficient to induce cellular senescence in primary fibroblasts. The specific aims of this proposal include the determination of the underlying molecular and cellular mechanisms by which Sin3B regulates senescence and prevent cancer progression in mammals. Specifically, we propose to identify the molecular events leading to Sin3B upregulation upon oncogenic stress, and determine how Sin3B upregulation induces cellular senescence (Aim 1); to investigate the contribution of Sin3B-induced senescence in the suppression of cellular transformation in fibroblasts (Aim 2); to test the hypothesis that Sin3B expression prevents prostate tumor progression in vivo (Aim 3). To do so, we will use a combination of molecular, cellular and biochemical approaches, as well as genetically engineered mouse models of cancer.

描述（由申请人提供）：细胞衰老是由不同应力触发的永久性细胞周期退出，最近已成为一种保障机制，以防止不受控制的增殖和在致癌过程中发生的有害基因改变的积累。在早期的人类癌症（包括肿瘤前列腺病变）中已经确定了细胞衰老的标志物，但随着肿瘤的发展而丧失。与衰老在预防肿瘤进展中的作用一致，小鼠模型中衰老途径基本成分的遗传失活导致癌症进展的加速。 尽管积累了证据表明其在肿瘤抑制中的生物学相关性，但基本的细胞衰老基础基础基本的分子碱基仍然难以捉摸。最近，通过异染色性化对促增殖基因的转录沉默已显示与永久性衰老相关的细胞周期出口相关。我们使用基因工程小鼠和细胞的初步结果表明，复制和致癌基因诱导的细胞衰老都需要组蛋白脱乙酰基酶（HDAC）相关的SIN3B蛋白。另外，SIN3B是在致癌应激时特异性诱导的，并且其过表达足以诱导原代成纤维细胞中的细胞衰老。该提案的具体目的包括确定SIN3B调节衰老并预防哺乳动物癌症进展的基本分子和细胞机制。具体而言，我们建议鉴定导致造成致力应激的SIN3b上调的分子事件，并确定SIN3B上调如何诱导细胞衰老（AIM 1）；研究SIN3B诱导的衰老在成纤维细胞中细胞转化抑制的贡献（AIM 2）；为了测试SIN3B表达的假设可防止前列腺肿瘤在体内的进展（AIM 3）。为此，我们将使用分子，细胞和生化方法以及癌症的基因工程小鼠模型的组合。