DDR1 in p53-mediated suppression and in breast cancer

描述(由申请人提供)：越来越多的证据表明，蛋白激酶或其相关信号通路的调节表达的扰动可能导致恶性转化。我们最近利用差异筛选技术鉴定了一个cDNA克隆为P53靶基因，该基因也对DNA损伤有反应。该克隆为DDR1/Cak1/TrkE/RTK6，编码一个新的受体酪氨酸激酶家族成员。虽然DDR1的生物学作用尚未确定，但通过p53和DNA损伤反式激活DDR1基因及其作为受体酪氨酸激酶的潜在功能是令人感兴趣的。我们的初步数据表明，与其他P53靶基因不同，DDR1K既可以作为细胞周期抑制因子，也可以作为细胞凋亡促进剂，它通过对抗P53介导的细胞死亡/凋亡来促进细胞存活。此外，在含wt-p53的细胞中，DDR1表达可诱导p53、p21和Arf/p19的表达，而在p53缺失或突变的细胞中则无此作用。这些结果表明，DDR1可能通过p53-DDR1-RAS/Raf/MAPK-P53模块的正反馈环来调节P53。我们的工作假设是，p53通过上调DDR1激活MAPK和/或AKT来促进细胞存活，并且抑制DDR1功能增强了p53诱导的细胞杀伤效应。DDR1可能是细胞调控开关的一部分，该开关决定细胞是经历停滞还是凋亡。在这项提案中，我们将讨论这些细胞结果是如何调控的，以及DDR1介导的MAPK/ERK激活是否参与并废除了P53/DNA损伤诱导的细胞凋亡。更好地理解DDR1R的作用(S)将提供一个独特的机会，研究P53介导的肿瘤抑制的新机制，并开发新的靶向具有正常P53功能的人类肿瘤的方法，包括抑制DDR1R信号转导。

DESCRIPTION (provided by applicant): Accumulating evidence indicate that perturbations in the regulated expression of protein kinases or their associated signaling pathways can lead to malignant transformation. We have recently identified a cDNA clone as a p53-target gene using differential screening, which was also responsive to DNA damage. This clone, DDR1/Cak1/TrkE/RTK6, encodes a novel family member of the receptor tyrosine kinases. Although the biological role of DDR1 has not yet been defined, transactivation of the DDR1 gene by p53 and DNA damage and its potential function as a receptor tyrosine kinase are intriguing. Our preliminary data suggest that, unlike other p53 target genes that function as either cell cycle inhibitors or apoptosispromoters, DDR1 kinase promotes cell survival by counteracting p53-mediated cell death/apoptosis. Moreover, DDR1 expression induced levels of p53, p21 and Arf/p19 in wt-p53 containing cells but not in p53-null or mutant cells. The findings suggest that DDR1 may function through a positive feed back loop of the p53-DDR1-Ras/Raf/MAPK-p53 module in the regulation of p53. Our working hypothesis is that p53 activates MAPK and/or AKT through DDR1 up-regulation to promote cell survival, and that inhibition of DDR1 function enhances the cell killing effects of p53 induction. DDR1 may be part of a cellular regulatory switch that dictates the cellular decision to undergo either arrest or apoptosis. In this proposal, we will address how these cellular outcomes are governed, and whether or not DDR1-mediated MAPK/ERK activation participates in and abrogates the p53/DNA damage-induced apoptosis. Better understanding of the role(s) of DDR1 should offer a unique opportunity to study a novel mechanism of p53-mediated tumor suppression and to develop novel approaches for targeting human cancers with normal p53 function, involving the inhibition of DDR1 receptor signaling.