Growth Control Regulated by p53 and Mdm2 on Chromatin

p53肿瘤抑制因子是一个重要的转录因子，在脊椎动物进化过程中一直高度保守。野生型p53蛋白作为细胞生长和细胞死亡的控制者。p53的负反馈调节因子Mdm2对维持发育至关重要。p53激活mdm2的表达，而mdm2蛋白反过来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的小组之一，证明Mdm2在人类细胞中与p53形成可溶性和染色质结合复合物。一些证据表明，这一过程体现了一个重要的基本转录调控程序，其中Mdm2影响因子向染色质的募集，以阻止功能性转录，但这一点尚未得到充分阐明。人类细胞系被用来研究p53-Mdm2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小组将基础研究与培养下一代多元文化和多民族科学家的强大的更广泛的影响目标结合起来。该项目的核心目标如下：1)确定Mdm2是否阻断p53靶基因的转录起始或延伸。2)表征Mdm2对p53靶基因组蛋白修饰的作用。3)在Mdm2过表达细胞培养模型中，确定Mdm2和p300是否作为p53转录因子的竞争对手。4)检测由Mdm2选择性剪接产生的Mdm2蛋白对染色质相关p53的调控。根据本项目获得的结果，将确定Mdm2替代形式影响p53转录活性、p300和PCAF募集以及局部和远端组蛋白修饰调控的能力。5)将科研与教学结合起来，激发多民族的下一代科学工作者。该项目由Bargonetti实验室小组进行，将研究和教学结合起来，作为激发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在多元文化环境中进行研究并由Bargonetti博士指导，该环境为所有人设定了高标准，并期望相互尊重所有文化。所有参与该项目的学生都被鼓励进入著名的博士项目、博士后职位和终身教职。

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.