Cellular Responses to p53 Activation by Nutlin-3a

项目概要/摘要： 野生型p53是一种有效的肿瘤抑制因子，可被DNA损伤和其他应激激活。一直 作为一种治疗策略，恢复野生型p53的功能一直受到相当大的关注。这一目标导致 Nutlin-3（Nutlin）是一种通过阻断野生型p53的表达来激活野生型p53的小分子， MDM 2是细胞中p53活性的主要负调节因子。值得注意的是，Nutlin激活p53 通过非遗传毒性机制，因此其作为治疗剂的用途可以使组织免于有害的 与常见的DNA损伤药物相关的副作用。有效使用Nutlin要求其对 细胞被完全理解。我们已经研究了各种p53野生型细胞系对短暂的 Nutlin治疗。我们发现Nutlin激活p53可以促进细胞生长停滞或凋亡 依赖于生存途径的激活，我们已经确定了一个候选的生存因子， Nutlin诱导的细胞凋亡。我们还发现Nutlin对细胞骨架组织有惊人的影响 和控制DNA核内复制。该补助金的目的是确定Nutlin介导的 p53激活对这些不同的细胞反应的影响。

Project Summary / Abstract: Wild-type p53 is a potent tumor suppressor that is activated by DNA damage and other stresses. There has been considerable interest in restoring wild-type p53 function as a therapeutic strategy. This goal has led to the development of the Nutlin-3 (Nutlin), a small molecule that activates wild-type p53 by blocking its interaction with MDM2, the primary negative regulator of p53 activity in cells. Notably, Nutlin activates p53 through a non-genotoxic mechanism, and thus its use as a therapeutic agent may spare tissues of deleterious side-effects associated with common DNA damaging drugs. Effective use of Nutlin requires that its effects on cells be fully understood. We have examined the response of various p53 wild-type cell lines to transient Nutlin treatment. We find that p53 activation by Nutlin can promote growth arrest or apoptosis in cells dependent on activation of survival pathways, and we have identified a candidate survival factor that protects cells from Nutlin-induced apoptosis. We also find that Nutlin has surprising effects on cytoskeletal organization and control of DNA endoreduplication. The purpose of this grant is to determine the effects of Nutlin-mediated p53 activation on these various cellular responses.