Oncogenic functions of mutant p53

摘要 肿瘤抑制基因p53具有抑制肿瘤发展的多效性功能。 它最重要的功能之一是防止基因组遭受DNA损伤 以防止遗传损伤扩散到子代细胞。鉴于……的高度 对于癌症中的基因改变，P53经常失活也就不足为奇了。最多的 P53基因常见的遗传损伤形式是DNA结合域的点突变。 这些错义突变通常使P53‘S肿瘤抑制活性失活，而 同时产生致癌蛋白。突变型P53的存在与 染色体不稳定性增加导致肿瘤抑制基因丢失和基因扩增 致癌基因。人们越来越认识到，cGAS/STING/TBK1/IRF3与生俱来 免疫反应信号通路在检测基因改变和基因突变中发挥关键作用 启动细胞内在和外在反应以抑制携带遗传基因的异常细胞 缺陷。在这个提议中，我们发现突变型p53抑制了通过cGAS/STIN传递的信号 途径，从而决定细胞如何对其激活作出反应。我们提出三个目标来 确定突变型p53控制cGAS/STING信号转导的机制，以及细胞 调节这一途径的内在和外在后果。这些项目的完成 研究将有助于指导如何根据癌症的P53状态进行治疗。

Abstract The tumor suppressor gene, p53, has pleiotropic functions that quash tumor development. One of its most important functions is to prevent the genome from sustaining DNA damage in order to prevent the propagation of genetic lesions into daughter cells. Given the high degree of genetic alterations in cancer, it is not surprising that p53 is frequently inactivated. The most common form of genetic lesions in the p53 gene are point mutations in the DNA binding domain. These missense mutations typically inactivate the p53’s tumor suppressor activity while simultaneously generating an oncogenic protein. The presence of mutant p53 correlates with increased chromosomal instability leading to loss of tumor suppressor genes and amplification of oncogenes. It has become increasingly recognized that the cGAS/STING/TBK1/IRF3 innate immune response signaling pathway plays a crucial role in detecting genetic alterations and launching cell intrinsic and extrinsic responses to suppress aberrant cells that harbor genetic defects. In this proposal, we that mutant p53 suppresses signaling through the cGAS/STING pathway and thereby dictates how cells respond to its activation. We propose three aims to determine the mechanism by which mutant p53 controls cGAS/STING signaling, and the cell intrinsic and extrinsic consequences of modulation of this pathway. The completion of these studies will help guide how to therapeutically approach cancers based on their p53 status.