Modulation of p53 function by tyrosine kinase networks

描述（由申请人提供）：在几乎一半的人类癌症中，p53的失活是由调控失常而不是基因突变引起的。更好地了解这种p53失活的机制不仅可以为肿瘤发生提供新的见解，还可以为癌症治疗提供恢复p53功能的策略。认识到解除调节的酪氨酸激酶（TK）信号在肿瘤发生和癌症治疗抵抗中的普遍存在，我们通过关注MDM2/MDMX复合物来寻找能够干扰p53通路的潜在TK，因为我们最近的遗传研究表明，这两种必要的p53抑制剂在p53控制中共同起作用。通过筛选TK库，确定了一些候选基因，并证实了它们对MDM2/MDMX复合物和p53活性的影响。我们假设致癌TKs至少在一定程度上通过撞击MDM2/MDMX复合物使p53失活，从而促进肿瘤发生和治疗耐药性（图1）。这项工作将使用体外和体内模型来功能表征tk介导的MDM2/MDMX复合物在p53调控背景下的调节。我们还将探索使用TK抑制剂（TKIs）来恢复p53功能，以提高癌症治疗的疗效。提出了三个具体目标：1)表征tks介导的MDM2/MDMX复合物的调节。2)确定tks诱导的MDM2/MDMX复合物改变的体内生物学相关性。3)探讨通过抑制TKs恢复p53功能的治疗意义。

DESCRIPTION (provided by applicant): Inactivation of p53 in almost half of human cancer is caused by aberrations in regulation rather than gene mutation. A better understanding of the mechanisms underlying such p53 inactivation will not only offer new insight into tumorigenesis but also enable the development of strategies to restore p53 function for cancer therapeutics. Recognizing the prevalence of deregulated tyrosine kinase (TK) signaling in tumorigenesis and cancer therapy resistance, we searched for potential TKs able to interfere with the p53 pathway by focusing on the MDM2/MDMX complex because our recent genetic study demonstrated that these two essential p53 inhibitors function together in p53 control. By screening a TK library, a number of candidates were identified and their effect on the MDM2/MDMX complex and p53 activity was confirmed. We hypothesize that oncogenic TKs inactivate p53 at least in part by impinging on the MDM2/MDMX complex, leading to promotion of tumorigenesis and therapeutic resistance (Fig. 1). The proposed work will use both in vitro and in vivo models to functionally characterize TK-mediated modulation of the MDM2/MDMX complex in the context of p53 regulation. We will also explore the use of TK inhibitors (TKIs) to restore p53 function for improving cancer therapeutics efficacy. Three specific aims are proposed: 1) To characterize TKs-mediated modulation of the MDM2/MDMX complex. 2) To determine in vivo biological relevance of TKs-induced alteration of the MDM2/MDMX complex. 3) To explore the therapeutic implications of restoring p53 function via inhibition of TKs.