Molecular Oncogenic Properties of Mutant p53

描述（由申请人提供）：本申请旨在研究突变型p53的分子致癌特性。p53肿瘤抑制因子是一种序列特异性dna结合转录因子。野生型p53在各种应激信号下被激活，如DNA损伤、癌基因激活和缺氧。激活后，p53通过诱导下游效应，如细胞周期阻滞和细胞凋亡，抑制受损细胞增殖。然而，p53基因的突变剥夺了其转录活性，导致肿瘤细胞不受控制的增殖特征。因此，超过50%的人类癌症都是由p53基因突变导致的。绝大多数p53突变发生在其DNA结合域，使p53的DNA结合和转录活性出现缺陷。这代表了典型的肿瘤抑制基因的功能突变丧失。有趣的是，除了功能丧失之外，许多p53突变体还获得了额外的活性，称为功能获得。众所周知，在同时携带野生型和突变型p53的细胞中，突变型p53通过与野生型p53形成异源四聚体并抑制其活性来获得功能增益。然而，绝大多数过表达突变型p53的肿瘤细胞不携带野生型p53。因此，突变型p53在这些肿瘤细胞中获得功能一定是由于其独立于野生型p53抑制的促瘤活性。为了进一步分析突变型p53是如何获得其功能增益的，我们提出了以下具体目标：(1)确定突变型p53是否需要维持肿瘤细胞的转化表型以逃避凋亡和增强增殖和侵袭的潜力；(2)确定不同类型的p53突变体维持肿瘤细胞转化表型的能力是否存在差异；(3)确定突变后的p53是否仍然作为转录因子调控促进生存或抑制抗生长信号的基因。

DESCRIPTION (provided by applicant): This application is proposed to address the molecular oncogenic properties of mutant p53. p53 tumor suppressor is a sequence-specific DNA-binding transcription factor. Wild-type p53 is activated in response to various stress signals, such as DNA damage, oncogene activation, and hypoxia. Following its activation, p53 suppresses damaged cells to proliferate by inducing downstream effects, such as cell cycle arrest and apoptosis. However, mutations in the p53 gene abrogate its transcriptional activity, leading to the uncontrolled proliferation characteristic of tumor cells. As a result, mutations of the p53 gene are selected for in greater than 50% of all human cancers. A vast majority of p53 mutations occur in its DNA-binding domain, rendering p53 defective in its DNA binding and transcriptional activities. This represents the classical loss of function mutation for a tumor suppressor. Interestingly, in addition to loss of function, many p53 mutants obtain additional activities, called gain of function. It is well known that in a cell carrying both wild-type and mutant p53, the mutant p53 acquires its gain of function by forming a heterotetramer with, and inhibiting the activity of, wild-type p53. However, the vast majority of tumor cells, which over-express a mutant p53, do not carry a wild-type p53. Thus, mutant p53 gain of function in these tumor cells must be due to its tumor-promoting activity independent of the inhibition of wild-type p53. To further analyze how mutant p53 obtains its gain of function, the following specific aims are proposed: (1) to determine whether mutant p53 is required for maintaining the transformed phenotypes of tumor cells in evading apoptosis and enhanced potentials in proliferation and invasion; (2) to determine whether various classes of p53 mutants differ in their ability to maintain the transformed phenotypes of tumor cells; and (3) to determine whether mutant p53 still functions as a transcription factor that regulates genes involved in promoting survival or inhibiting anti-growth signals.