Modulation of p53 function by tyrosine kinase networks

描述（由申请人提供）：几乎一半的人类癌症中p53的失活是由调节异常而不是基因突变引起的。更好地理解这种p53失活的机制不仅可以为肿瘤发生提供新的见解，而且还可以开发恢复p53功能的癌症治疗策略。认识到酪氨酸激酶（TK）信号转导失调在肿瘤发生和癌症治疗耐药性中的普遍性，我们通过关注MDM 2/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学研究表明，这两种必需的p53抑制剂在p53控制中一起起作用。通过筛选TK文库，鉴定了许多候选物，并证实了它们对MDM 2/MDMX复合物和p53活性的作用。我们假设致癌TK至少部分通过冲击MDM 2/MDMX复合物而抑制p53，导致肿瘤发生和治疗抗性的促进（图1）。拟议的工作将使用体外和体内模型来功能性地表征TK介导的MDM 2/MDMX复合物在p53调节背景下的调节。我们还将探索使用TK抑制剂（TKI）来恢复p53功能，以提高癌症治疗效果。提出了三个具体目标：1）表征TK介导的MDM 2/MDMX复合物的调节。2)确定TK诱导的MDM 2/MDMX复合物改变的体内生物学相关性。3)探讨通过抑制TK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.