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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-PTHB (01))
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Blair, Donald G
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Massachusetts General Hospital
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