Regulation of E2-Induced Senescence

这是一个由迪马约博士领导的正在进行的项目。衰老是一种重要的肿瘤抑制因子 机制。衰老似乎不仅可以防止体内肿瘤的形成，而且有可能 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， 我们开发了一种新的由人类转录抑制诱导的细胞衰老模型 宫颈癌细胞系中乳头瘤病毒癌基因的研究。与大多数其他衰老模型相比， HPV抑制引起的衰老是快速、均匀和同步的。我们将使用此模型来 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抑制引起的最初生长停滞转变为不可逆转的衰老状态。我们 将检验这一假设，即异染色质在被抑制的启动子上的稳定组装是主要的 不可逆性的原因。我们将使用这个系统来确定这种抑制的异染色质是如何形成的， 我们将进行基因筛查，以确定具有逆转衰老能力的细胞基因 单独或与重新表达的病毒癌基因协同逆转衰老。第二，我们将 进行全面的遗传学和生物化学分析细胞微RNA在决定 衰老细胞的衰老表型和细胞基因表达模式。在协作中 与斯泰茨博士一起，我们将比较两种不同生长停滞状态下的microRNAs活性，衰老和 宁静。综上所述，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，并可能为尝试翻译这一点奠定基础 了解通过调节衰老反应来治疗或预防癌症的合理新方法。

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.