MARC Predoctoral Fellowship

描述（由申请人提供）：p53激活细胞周期和凋亡基因对于控制或消除可能对整个生物体构成威胁的细胞至关重要。因此，这些基因的激活必须被巧妙地调节，因为它们只能在特殊情况下被激活。我建议的目标是了解p53对应激的转录反应机制，以及这在影响细胞命运方面可能发挥的作用。具体目的如下：1。当细胞周期阻滞和促凋亡p53靶基因在各种应激反应中组装时，转录机制的组成和功能是什么？2. 哪些p53辅助因子（包括修饰p53的酶）需要帮助细胞在应激反应中决定命运？3. p63和p73的各种剪接变体在p53靶基因的应激激活调节中起什么作用？这些信息对于详细了解p53如何能够介导应激反应至关重要，并将有助于开发针对各种癌症的新疗法。

DESCRIPTION (provided by applicant): The activation of cell cycle and apoptotic genes by p53 is crucial in controlling or eliminating cells that may be a threat to the whole organism. The activation of these genes must therefore be cleverly regulated since they must only be activated under exceptional circumstances. The goal of my proposal is to understand the mechanisms of the transcriptional response to stress by p53 and how this may play a role in influencing the cells fate. The specific aims are as follows: 1. What is the composition and function of the transcriptional machinery when assembled on cell cycle arrest and pro-apoptotic p53 target genes in response to various stresses? 2. Which p53 cofactors (including enzymes that modify p53) are required to aid in cell fate decisions in response to stress? 3. What role do the various splice variants of p63 and p73 play with regards to stress activated regulation of p53 target genes? This information will be critical for a detailed understanding of how p53 is able to mediate stress responses and will aid in the development of new therapies for various cancers.