Regulation of Cellular Senescence and Oncogenic Transformation by Sin3B.

Sin3B 对细胞衰老和致癌转化的调节。

基本信息

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
项目类别：
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

项目摘要

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激触发的永久性细胞周期退出，最近已成为针对致癌转化过程中发生的不受控制的增殖和有害遗传改变积累的保护机制。细胞衰老的标志物已在早期人类癌症（包括前列腺癌前病变）中被发现，但随着肿瘤的进展而消失。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的重要组成部分的基因失活会导致癌症进展加速。尽管越来越多的证据表明其在肿瘤抑制中的生物学相关性，但细胞衰老建立的分子基础仍然很大程度上难以捉摸。最近，通过异染色质化促进增殖基因的转录沉默已被证明与永久衰老相关的细胞周期退出相关。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 在致癌应激下被特异性诱导，其过度表达足以诱导原代成纤维细胞的细胞衰老。该提案的具体目标包括确定 Sin3B 调节哺乳动物衰老和预防癌症进展的潜在分子和细胞机制。具体来说，我们建议确定导致 Sin3B 在致癌应激下上调的分子事件，并确定 Sin3B 上调如何诱导细胞衰老（目标 1）；研究 Sin3B 诱导的衰老在抑制成纤维细胞转化中的作用（目标 2）；检验 Sin3B 表达可阻止体内前列腺肿瘤进展的假设（目标 3）。为此，我们将结合使用分子、细胞和生化方法以及基因工程小鼠癌症模型。