Regulation of E2-Induced Senescence

这是一个正在进行的项目，由DiMaio博士领导。衰老是一种重要的肿瘤抑制因子 机制衰老不仅可以防止体内肿瘤的形成，而且可能 动员持久的衰老反应作为治疗癌症的新方法。在这笔赠款的支持下， 我们已经开发了一种新的细胞衰老模型，该模型是由人类基因组的转录抑制诱导的。 宫颈癌细胞系中的乳头瘤病毒癌基因。与大多数其他衰老模型相比， 由HPV抑制诱导的衰老是快速、均匀和同步的。我们将利用这一模式， 探索衰老的两个重要方面。首先，我们将确定分子机制， 由HPV E7抑制引起的初始生长停滞转变为不可逆的衰老状态。我们 将测试这一假设，异染色质在阻遏启动子的稳定组装是主要的 不可逆转的原因。我们将用这个系统来确定这种异染色质是如何形成的， 我们将进行基因筛选，以确定细胞基因的能力， 或与重新表达的病毒癌基因合作以逆转衰老。二是 对细胞microRNA在决定细胞增殖中的作用进行全面的遗传和生物化学分析， 衰老表型和衰老细胞中细胞基因表达的模式。合作 与Steitz博士一起，我们将比较两种不同生长停滞状态下microRNA的活性，衰老和 安静综合起来，这些实验将为分子机制提供新的见解 建立和维持衰老状态，并可能为试图将其转化为 通过调节衰老反应，将这些知识转化为合理的新方法来治疗或预防癌症。

This is an ongoing project headed by Dr. DiMaio. Senescence is an important tumor suppressor mechanism. Not only does senescence appear to prevent tumor formation in vivo, but it may be possible to mobilize a durable senescence response as a new approach to treat cancer. With the support of this grant, we have developed a new model of cellular senescence induced by transcriptional repression of the human papillomavirus oncogenes in cervical carcinoma cell lines. In contrast to most other models of senescence, senescence induced by HPV repression is rapid, uniform, and synchronous. We will use this model to explore two important aspects of senescence. First, we will determine the molecular mechanism by which the initial growth arrest caused by HPV E7 repression is converted to an irreversible senescent state. We will test the hypothesis that the stable assembly of heterochromatin at repressed promoters is the primary cause of irreversibility. We will use this system to determine how this ~epressive heterochromatin is formed, and we will conduct a genetic screen to identify cellular genes with the ability to either reverse senescence on their own or to cooperate with re-expressed viral oncogenes to reverse senescence. Second, we will conduct a comprehensive genetic and biochemical analysis of the role of cellular microRNAs in determining the senescence phenotype and the pattern of cellular gene expression in senescent cells. In collaboration with Dr. Steitz, we will compare microRNAs activity in two different growth-arrested states, senescence and quiescence. Taken together, these experiments will provide new insights into the molecular mechanisms that establish and maintain the senescent state, and may set the stage for attempts to translate this knowledge into rational new approaches to treat or prevent cancer by modulating the senescence response.