Regulation of Cellular Senescence and Oncogenic Transformation by Sin3B.

描述（由申请人提供）：细胞衰老是一种由不同应激触发的永久性细胞周期退出，最近已成为防止致癌转化期间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经在早期人类癌症中被鉴定，包括癌前前列腺病变，但是随着肿瘤的进展而丢失。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基本组分的遗传失活导致癌症进展的加速。 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在很大程度上仍然难以捉摸。最近，通过异染色质化的促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，组蛋白去乙酰化酶（HDAC）相关的Sin 3B蛋白是复制和癌基因诱导的细胞衰老所必需的。此外，Sin 3B在致癌应激时被特异性诱导，并且其过表达足以诱导原代成纤维细胞中的细胞衰老。该提案的具体目标包括确定Sin 3B调节衰老和预防哺乳动物癌症进展的潜在分子和细胞机制。具体来说，我们建议确定致癌应激时导致Sin 3B上调的分子事件，并确定Sin 3B上调如何诱导细胞衰老（目标1）;研究Sin 3B诱导的衰老在抑制成纤维细胞细胞转化中的贡献（目标2）;测试Sin 3B表达在体内阻止前列腺肿瘤进展的假设（目标3）。为此，我们将结合使用分子、细胞和生物化学方法，以及基因工程小鼠癌症模型。

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.