Growth Control Regulated by p53 and Mdm2 on Chromatin

染色质上的 p53 和 Mdm2 调节生长控制

• 批准号: 0744316
• 负责人: Jill Bargonetti
• 金额: $ 49.25万
• 依托单位: CUNY Hunter College
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0744316&HistoricalAwards=false
• 关键词: Growth; Control; Regulated; p53; Mdm2

The p53 tumor suppressor is an important transcription factor that has been highly conserved throughout vertebrate evolution. The wild-type p53 protein acts as a controller of cell growth and cell death. The negative feedback regulator of p53, Mdm2, is critically important to sustain development. p53 activates expression of mdm2 and the Mdm2 protein in turn inactivates p53 by either repressing its transcriptional activity or facilitating its degradation by the proteasome. The Bargonetti laboratory and colleagues are among only a few groups that have provided evidence that Mdm2 forms both soluble as well as chromatin-bound complexes with p53 in human cells. Several lines of evidence suggest that this process exemplifies an important basic transcription regulation program where Mdm2 influences the recruitment of factors to chromatin to prevent functional transcription, but this has yet to be fully elucidated. Human cell lines are used to investigate the chemical nature and function of p53-Mdm2 chromatin-associated complexes and their impact on transcription. The Bargonetti group is carrying out basic research in combination with a strong broader impact objective to produce the next generation of multicultural and multiethnic scientists. The core objectives of the project are the following: 1) Determine if Mdm2 blocks transcription initiation or elongation at p53 target genes. 2) Characterize the role of Mdm2 on histone modifications at p53 target genes. 3) Determine if Mdm2 and p300 act as competitors for the p53 transcription factor in Mdm2 over-expression cell culture models. 4) Examine the regulation of chromatin-associated p53 by Mdm2 proteins produced from alternatively spliced mdm2. Based on the results obtained from this project the ability of the alternate forms of Mdm2 to influence p53 transcriptional activity, recruitment of p300 and PCAF, and regulation of local and distal histone modification will be determined. 5) Integrate research and teaching as a method to excite the next generation, multiethnic, science work force.The project being carried out by the Bargonetti laboratory group integrates research and teaching as a method to excite the next generation, multiethnic, science work force. Undergraduate students as well as graduate students are part of the research team. Under-represented minority students, as well as non-minority students, carry out the research and are mentored by Dr. Bargonetti in a multicultural environment where high standards are set for all and mutual respect for all cultures is the expectation. All students participating in this project are encouraged to move on to notable Ph.D. programs, post-doctoral positions and tenure track faculty jobs.

p53肿瘤抑制因子是一种重要的转录因子，在脊椎动物进化过程中高度保守。野生型p53蛋白充当细胞生长和细胞死亡的控制器。p53的负反馈调节因子Mdm 2对维持发育至关重要。p53激活mdm 2的表达，而Mdm 2蛋白又通过抑制其转录活性或促进其被蛋白酶体降解而使p53失活。Bargonetti实验室及其同事是少数几个提供证据证明Mdm 2在人类细胞中与p53形成可溶性和染色质结合复合物的小组之一。一些证据表明，这一过程证实了一个重要的基本转录调控程序，其中Mdm 2影响因子向染色质的募集以阻止功能性转录，但这一点尚未完全阐明。人类细胞系用于研究p53-Mdm 2染色质相关复合物的化学性质和功能及其对转录的影响。Bargonetti集团正在开展基础研究，并结合强大的更广泛的影响目标，以培养下一代多文化和多种族的科学家。该项目的核心目标如下：1）确定Mdm 2是否阻断p53靶基因的转录起始或延伸。2)表征Mdm 2对p53靶基因组蛋白修饰的作用。3)确定Mdm 2和p300是否在Mdm 2过表达细胞培养模型中作为p53转录因子的竞争者。4)检查由选择性剪接mdm 2产生的Mdm 2蛋白对染色质相关p53的调节。基于从该项目获得的结果，将确定Mdm 2的替代形式影响p53转录活性、p300和PCAF的募集以及局部和远端组蛋白修饰的调节的能力。 5)将研究和教学结合起来，作为激励下一代多民族科学工作者的一种方法。由Bargonetti实验室小组开展的项目将研究和教学结合起来，作为激励下一代多民族科学工作者的一种方法。本科生和研究生都是研究团队的一部分。代表性不足的少数民族学生以及非少数民族学生进行研究，并在一个为所有人制定高标准和相互尊重所有文化的多元文化环境中得到Bargonetti博士的指导。鼓励所有参加这个项目的学生继续攻读著名的博士学位。项目、博士后职位和终身教职。