Modulation of p53 function by tyrosine kinase networks

描述(申请人提供)：在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。更好地了解这种p53失活的机制不仅将为肿瘤的发生提供新的见解，还将有助于为癌症治疗制定恢复p53功能的策略。认识到去调控的酪氨酸激酶(TK)信号在肿瘤发生和癌症治疗耐药中的普遍存在，我们通过关注MDM2/MDMX复合体来寻找能够干扰P53通路的潜在TKS，因为我们最近的遗传学研究表明，这两个基本的P53抑制物在P53控制中共同发挥作用。通过筛选TK文库，确定了一些候选基因，并证实了它们对MDM2/MDMX复合体和P53活性的影响。我们假设，致癌的TKS至少部分通过作用于MDM2/MDMX复合体而使p53失活，导致肿瘤发生和治疗耐药的促进(图1)。这项拟议的工作将使用体外和体内模型来功能表征TK介导的MDM2/MDMX复合体在p53调控的背景下的调节。我们还将探索使用TK抑制剂(TKI)来恢复P53功能，以提高癌症治疗的疗效。我们提出了三个具体的目标：1)研究TKS对MDM2/MDMX复合体的调控作用。2)确定TKS诱导MDM2/MDMX复合体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。 与公共卫生相关：由于我们的初步数据表明MDM复合体是许多TKS的靶标，该应用旨在描述TK信号网络诱导的该复合体的修改的功能特征，这有望揭示P53失活的新机制。尽管人们普遍观察到，去调控的TKS有助于癌症的发生和对癌症治疗的抵抗，但其潜在的机制尚未完全阐明。TKS通过影响MDM复合体来抑制P53的激活，可能是肿瘤发生和治疗耐药的新机制。我们的研究具有重要意义，因为它不仅提供了对解除管制的TK诱导的致癌作用的洞察，而且还为放化疗或化疗与TKI的联合使用提供了基础，这将恢复P53对化疗或放疗的反应性，从而提高治疗效果。

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. PUBLIC HEALTH RELEVANCE: With our preliminary data indicating the MDM complex as a target of a number of TKs, the application aims at functional characterization of TK signaling network-induced modifications of this complex, which is expected to uncover novel mechanisms of p53 inactivation. Even though it is widely observed that deregulated TKs contribute to carcinogenesis and resistance to cancer therapeutics, the underlying mechanisms are not yet fully elucidated. Impediment of p53 activation by the TKs via affecting the MDM complex would represent a novel mechanism of tumorigenesis and therapy resistance. Our study is significant as it would not only offer insight into deregulated TK-induced carcinogenesis but also provide a basis for a combined use of radio- or chemotherapy with TKIs, which would restore the responsiveness of p53 to chemo or radiotherapy, resulting in improved therapeutic efficacy.