DDR1 in p53-mediated suppression and in breast cancer

DDR1 在 p53 介导的抑制和乳腺癌中的作用

• 批准号: 7097402
• 负责人: SAM W LEE
• 金额: $ 30.42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097402
• 关键词: DNA damage; apoptosis; athymic mouse; biological signal transduction; breast neoplasms; cell cycle proteins; flow cytometry; mitogen activated protein kinase; neoplasm /cancer genetics; neoplastic transformation; p53 gene /protein; protein kinase; protein protein interaction; receptor; terminal nick end labeling; tissue /cell culture; tumor suppressor genes; yeast two hybrid system

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.

描述（由申请人提供）：积累证据表明蛋白激酶的调节表达表达或其相关信号传导途径的扰动可能导致恶性转化。我们最近使用鉴别筛选确定了cDNA克隆为p53靶基因，这也对DNA损伤有反应。该克隆，DDR1/CAK1/TRKE/RTK6编码了受体酪氨酸激酶的新型家庭成员。尽管尚未定义DDR1的生物学作用，但通过p53和DNA损伤对DDR1基因的反式激活及其作为受体酪氨酸激酶的潜在功能令人着迷。我们的初步数据表明，与其他用作细胞周期抑制剂或凋亡促进剂的p53靶基因不同，DDR1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，DDR1表达在WT-P53中诱导p53，p21和arf/p19的水平，但在p53-null或突变细胞中诱导了水平。研究结果表明，DDR1可以通过p53调节中的p53-DDR1-RAS/RAF/MAPK-p53模块的正馈回循环发挥作用。我们的工作假设是，p53通过DDR1上调激活MAPK和/或AKT以促进细胞存活，并且抑制DDR1功能会增强p53诱导的细胞杀伤作用。 DDR1可能是细胞调节开关的一部分，该开关决定了细胞的决定要么被停滞或凋亡。在此提案中，我们将解决这些细胞结局的控制，以及DDR1介导的MAPK/ERK激活是否参与并消除了p53/DNA损伤诱导的凋亡。更好地了解DDR1的作用应提供一个独特的机会来研究p53介导的肿瘤抑制的新机制，并开发用于靶向具有正常p53功能的人类癌症的新方法，涉及抑制DDR1受体信号传导。