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Cellular Responses to p53 Activation by Nutlin-3a

Nutlin-3a 激活 p53 的细胞反应

基本信息

批准号：
8471662
负责人：
Carl G Maki
金额：
$ 28.38万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-13 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8471662
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

项目摘要

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.

项目概要/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。一直作为一种治疗策略，恢复野生型p53的功能一直受到相当大的关注。这一目标导致 Nutlin-3（Nutlin）是一种通过阻断野生型p53的表达来激活野生型p53的小分子， MDM 2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 通过非遗传毒性机制，因此其作为治疗剂的用途可以使组织免于有害的与常见的DNA损伤药物相关的副作用。有效使用Nutlin要求其对细胞被完全理解。我们已经研究了各种p53野生型细胞系对短暂的 Nutlin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素，可以保护 Nutlin诱导的细胞凋亡。我们还发现Nutlin对细胞骨架组织有惊人的影响和控制DNA核内复制。该补助金的目的是确定Nutlin介导的 p53激活对这些不同的细胞反应的影响。