Cellular Responses to p53 Activation by Nutlin-3a

描述(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的功能作为一种治疗策略很感兴趣。这一目标导致了Nutlin-3(Nutlin)的开发，Nutlin-3是一种小分子，通过阻断野生型p53与细胞中p53活性的主要负调节因子MDM2的相互作用来激活它。值得注意的是，Nutlin通过一种非遗传毒性机制激活P53，因此将其用作治疗剂可能使组织免于与常见DNA破坏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。我们已经检测了不同的p53野生型细胞系对瞬时Nutlin治疗的反应。我们发现由Nutlin激活的P53可以促进依赖于生存通路激活的细胞的生长停滞或凋亡，我们已经确定了一个候选的生存因子来保护细胞免受Nutlin诱导的细胞凋亡。我们还发现，Nutlin在细胞骨架组织和DNA内复制控制方面具有惊人的效果。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。 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；有加速细胞生长的加速器和防止细胞生长过快的刹车。P53蛋白是防止正常细胞变成癌症的重要细胞刹车，而P53在大多数人类癌症中都是不活跃的。我们正在研究Nutlin-3a对P53激活的影响，Nutlin-3a是一种小分子，在一组癌症中特异性地激活野生型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.