Cellular Responses to p53 Activation by Nutlin-3a

Nutlin-3a 激活 p53 的细胞反应

• 批准号: 8271293
• 负责人: Carl G Maki
• 金额: $ 30.19万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-13 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271293
• 关键词: Actins; Adverse effects; Aneuploid Cells; Aneuploidy; Apoptosis; Automobile Driving; Biological Assay; Breast Cancer Cell; Cancer cell line; Cell Line; Cells; Chromosomes; Cisplatin; Collection; Cytoskeletal Modeling; DNA; DNA Damage; DNA biosynthesis; Data; Development; Dose; Epithelial Cells; Excision; Family; Focal Adhesions; G1 Arrest; Generations; Genomic Instability; Glucocorticoid Receptor; Goals; Grant; Growth; Guanosine Triphosphate Phosphohydrolases; HCT116 Cells; Human; Invaded; M cell; MDM2 gene; MYC gene; Malignant Neoplasms; Mammary gland; Mediating; Mitosis; Normal Cell; Pathway interactions; Pharmaceutical Preparations; Polyploid Cells; Protein p53; RU-486; Radiation; Receptor Activation; Reporting; Resistance; Signal Transduction; Stress; Stress Fibers; Testing; Therapeutic; Therapeutic Agents; Tissues; Tumor Suppressor Proteins; abstracting; anticancer research; base; cancer cell; cancer therapy; carcinogenesis; cell growth; cell motility; cell type; immortalized cell; in vivo; interest; killings; matrigel; migration; nutlin 3; prevent; response; rho; small molecule; wound

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.

项目摘要/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。有 人们对恢复野生型 p53 功能作为一种治疗策略非常感兴趣。这个目标导致了 Nutlin-3 (Nutlin) 的开发，这是一种通过阻断野生型 p53 来激活野生型 p53 的小分子 与 MDM2 相互作用，MDM2 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 通过非基因毒性机制，因此将其用作治疗剂可以使组织免受有害物质的侵害 与常见 DNA 损伤药物相关的副作用。 Nutlin 的有效使用需要其对 细胞得到充分的了解。我们检查了各种 p53 野生型细胞系对瞬时 努特林治疗。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生存因子，可以保护 Nutlin 诱导的细胞凋亡。我们还发现 Nutlin 对细胞骨架组织具有令人惊讶的影响 以及DNA核内复制的控制。这笔赠款的目的是确定 Nutlin 介导的效果 p53 激活对这些不同的细胞反应的影响。