MODULATORS AND EFFECTORS OF MDM2 AND P53

MDM2 和 P53 的调节子和效应子

• 批准号: 6514829
• 负责人: DONNA L GEORGE
• 金额: $ 27.37万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514829
• 关键词: apoptosis; cell growth regulation; intracellular transport; oncoproteins; p53 gene /protein; protein structure function; protein transport; reporter genes; site directed mutagenesis; tissue /cell culture; transcription factor; tubulin; ubiquitin

DESCRIPTION: (Adapted from the investigator's abstract) The p53 protein plays a critical role in tumor suppression, and represents a pivotal mediator of cellular response to physiological stress. One of the major regulators of p53 activity and abundance is the MDM2 oncoprotein. The long-term goals of this research are to better understand the complex regulation of the p53 tumor suppressor and the MDM2 oncogene, specifically regarding interacting factors that modulate p53 function. In normal cells, p53 has a short half-life and its abundance is low. In response to cellular stress, p53 becomes stabilized and activated as a transcription factor, and the expression levels of p53-target genes increase of decrease. The physiological outcome of such p53 activation is growth arrest or cell death (apoptosis). Thus, elucidation of the parameters that control p53 abundance and function in a cell remains an important area of study in cancer biology. They have identified two proteins that can regulate the activity and stability of p53 when bound. One of these factors, the co-repressor mSin3A (Sin3), was previously determined by them to be a critical mediator of p53-dependent trans-repression and apoptosis. Thus, p53 transcriptional repression activity and stabilization may be functionally linked. The other factor, MDMX, is a homologue of the MDM2 oncoprotein. While MDMX stabilizes p53 by interfering with MDM2-mediated degradation of p53, Sin3 appears to stabilize p53 by a novel mechanism, not dependent on MDM2. The broad aims of this proposal are to elucidate the mechanisms whereby interaction with MDMX and Sin3 influence p53 regulation. Significantly, they have found that Sin3 can bind the p53 homologue p73 as well. This indicates that transcriptional repression and stabilization by interaction with Sin3 may be conserved properties of the family of p53-related transcription factors, with implications for understanding pathways of apoptosis. Therefore, as a natural corollary to this work, this hypothesis will also be tested.

描述：(改编自研究人员的摘要)P53蛋白发挥着 在肿瘤抑制中的关键作用，并代表了一个关键的中介 细胞对生理压力的反应。P53的主要调节者之一 活性和丰度是MDM2癌蛋白。这样做的长期目标是 研究是为了更好地了解p53肿瘤的复杂调控 抑制子和MDM2癌基因，特别是关于相互作用的因素 来调节P53的功能。在正常细胞中，P53的半衰期很短，其 丰度很低。作为对细胞压力的反应，P53变得稳定并 作为转录因子被激活，以及P53-靶基因的表达水平 基因的增加或减少。这种P53激活的生理结果是 生长停滞或细胞死亡(细胞凋亡)。因此，对参数的解释 控制细胞中P53丰度和功能仍然是 研究癌症生物学。他们已经确定了两种可以调节 结合时P53的活性和稳定性。其中一个因素是， 共抑制因子mSin3A(Sin3)，此前被他们确定为一个关键的 P53依赖的反式抑制和细胞凋亡的中介物。因此，P53 转录抑制活性和稳定性可能在功能上 已链接。另一种因子MDMX是MDM2癌蛋白的同源物。而当 MDMX通过干扰MDM2介导的P53、SIN3的降解来稳定P53 似乎通过一种新的机制稳定P53，而不依赖于MDM2。《博大》 这项建议的目的是阐明与 MDMX和SIN3影响P53的调控。值得注意的是，他们发现 SIN3也能与P53同源物p73结合。这表明， 与SIN3相互作用对转录的抑制和稳定可能是 P53相关转录因子家族的保守性质，与 对理解细胞凋亡途径的启示。因此，作为一种自然的 作为这项工作的必然结果，这一假设也将得到检验。