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导致恶性转化。我们最近已经确定了一个cDNA克隆作为p53靶基因，使用差异筛选，这也是响应DNA损伤。该克隆DDR 1/Cak 1/TrkE/RTK 6编码受体酪氨酸激酶的一个新家族成员。虽然DDR 1的生物学作用尚未确定，但p53和DNA损伤对DDR 1基因的反式激活及其作为受体酪氨酸激酶的潜在功能是有趣的。我们的初步数据表明，与其他p53靶基因作为细胞周期抑制剂或凋亡促进剂不同，DDR 1激酶通过抵消p53介导的细胞死亡/凋亡来促进细胞存活。此外，DDR 1的表达诱导p53，p21和Arf/p19的水平在wt-p53含有细胞，但不p53-null或突变细胞。结果提示，DDR 1可能通过p53-DDR 1-Ras/Raf/MAPK-p53模块的正反馈环调控p53的表达。我们的工作假设是，p53激活MAPK和/或AKT通过DDR 1上调，以促进细胞存活，并DDR 1功能的抑制增强p53诱导的细胞杀伤作用。DDR 1可能是细胞调节开关的一部分，其指示细胞决定经历停滞或凋亡。在这个建议中，我们将解决这些细胞的结果是如何管理的，以及是否DDR 1介导的MAPK/ERK激活参与并消除p53/DNA损伤诱导的细胞凋亡。更好地理解DDR 1的作用将为研究p53介导的肿瘤抑制的新机制和开发靶向具有正常p53功能的人类癌症的新方法提供独特的机会，包括抑制DDR 1受体信号传导。

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.