Cellular Responses to p53 Activation by Nutlin-3a

描述（由申请人提供）：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。恢复野生型p53功能作为一种治疗策略已经引起了相当大的兴趣。这一目标导致了Nutlin-3（Nutlin）的开发，Nutlin-3是一种通过阻断野生型p53与MDM 2（细胞中p53活性的主要负调节因子）的相互作用来激活野生型p53的小分子。值得注意的是，Nutlin通过非遗传毒性机制激活p53，因此其作为治疗剂的用途可以使组织免于与常见DNA损伤药物相关的有害副作用。有效使用Nutlin需要充分了解其对细胞的影响。我们已经研究了各种p53野生型细胞系对瞬时Nutlin治疗的反应。我们发现Nutlin激活p53可以促进依赖于生存途径激活的细胞生长停滞或凋亡，并且我们已经确定了一种保护细胞免受Nutlin诱导的凋亡的候选生存因子。我们还发现Nutlin对细胞骨架组织和DNA内复制的控制具有令人惊讶的作用。这项研究的目的是确定Nutlin介导的p53激活对这些不同细胞反应的影响。 公共卫生相关性：项目叙述：细胞生长可以被认为类似于驾驶汽车;有加速器可以加速细胞生长，刹车可以防止细胞生长过快。p53蛋白是一种重要的细胞制动器，可以防止正常细胞变成癌症，而p53在大多数人类癌症中是无活性的。我们正在研究Nutlin-3a对p53激活的影响，Nutlin-3a是一种小分子，可以特异性激活癌症亚组中的野生型p53。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Project Narrative: Cell growth can be considered similar to driving a car; there are accelerators that increase cell growth and brakes that prevent cells from growing too fast. The p53 protein is an important cell brake that prevents normal cells from becoming cancer, and p53 is inactive in most human cancers. We are studying the effects of p53 activation by Nutlin-3a, a small molecule that specifically activates wild-type p53 in a subset of cancers.