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。人们对恢复野生型p53功能作为一种治疗策略非常感兴趣。这一目标导致了Nutlin-3 （Nutlin）的发展，这是一种通过阻断野生型p53与MDM2（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通过一种非基因毒性机制激活p53，因此它作为一种治疗药物可能会使组织免受与普通DNA损伤药物相关的有害副作用。Nutlin的有效使用需要充分了解其对细胞的影响。我们已经检测了多种p53野生型细胞系对瞬时Nutlin处理的反应。我们发现，Nutlin激活p53可以促进依赖于存活途径激活的细胞的生长停滞或凋亡，并且我们已经确定了一个候选存活因子，可以保护细胞免受Nutlin诱导的凋亡。我们还发现Nutlin对细胞骨架组织和DNA内复制的控制有惊人的影响。这项资助的目的是确定nutlin介导的p53激活对这些不同细胞反应的影响。

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.