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: 8040517
• 负责人: Gregory David
• 金额: $ 35.07万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8040517
• 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. PUBLIC HEALTH RELEVANCE: Cellular senescence represents a driving force for aging as well as a barrier against cancer. We have identified Sin3B as a new and essential regulator of cellular senescence. Understanding the molecular basis for its role in the prevention of tumor progression has important implications for human health.

描述(申请人提供)：细胞衰老，一种由不同压力触发的永久性细胞周期退出，最近作为一种保护机制出现，既防止了不受控制的增殖，也防止了在致癌转化过程中发生的有害遗传变化的积累。细胞衰老的标志物已经在包括前列腺癌前病变在内的早期人类癌症中被发现，但随着肿瘤的进展而消失。与衰老在防止肿瘤进展中的作用一致，在小鼠模型中，衰老途径的基本成分的遗传失活会导致癌症进展的加速。尽管越来越多的证据表明它在抑制肿瘤中具有生物学相关性，但建立细胞衰老的分子基础在很大程度上仍然难以捉摸。最近，通过异染色质作用抑制促增殖基因的转录已被证明与永久性衰老相关的细胞周期退出有关。我们使用基因工程小鼠和细胞的初步结果表明，组蛋白脱乙酰酶(HDAC)相关的Sin3B蛋白是复制和癌基因诱导的细胞衰老所必需的。此外，Sin3B是在致癌压力下特异性诱导的，其过表达足以诱导原代成纤维细胞的细胞衰老。这项建议的具体目标包括确定Sin3B调节哺乳动物衰老和防止癌症进展的潜在分子和细胞机制。具体地说，我们建议确定在致癌压力下导致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诱导的衰老在抑制成纤维细胞细胞转化中的作用(Aim 2)；检验Sin3B表达阻止体内前列腺癌进展的假说(Aim 3)。为了做到这一点，我们将使用分子、细胞和生化方法的组合，以及通过基因工程构建的癌症小鼠模型。 与公共健康相关：细胞衰老是衰老的驱动力，也是抗癌的屏障。我们已经确定Sin3B是一种新的、必不可少的细胞衰老调节因子。了解其在预防肿瘤进展中作用的分子基础对人类健康具有重要意义。