Cellular Responses to p53 Activation by Nutlin-3a

项目摘要/摘要： 野生型p53是一种强大的肿瘤抑制因子，可被DNA损伤和其他应激激活。那里有 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)的研究进展，Nutlin是一种小分子，通过阻断野生型P53的表达而激活其活性。 与MDM2的相互作用，MDM2是细胞中P53活性的主要负调控因子。值得注意的是，Nutlin激活了P53 通过一种非遗传毒性机制，因此将其用作治疗剂可能会使有害组织 与常见的破坏DNA药物相关的副作用。有效使用Nutlin需要它对 细胞被充分理解。我们检测了不同的p53野生型细胞系对瞬变的反应。 努特林治疗。我们发现由Nutlin激活的P53可以促进细胞的生长停滞或凋亡 依赖于生存通路的激活，我们已经确定了一种候选生存因子，它可以保护 来自Nutlin的细胞诱导细胞凋亡。我们还发现，Nutlin对细胞骨架组织有惊人的影响 和DNA内复制的控制。这项资助的目的是确定由Nutlin介导的 P53的激活对这些不同的细胞反应。

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.