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- Title
p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop.
- Authors
Ongusaha, Pat P.; Kim, Jong-il; Li Fang; Wong, Tai W.; Vancopoulos, George D.; Aaronson, Stuart A.; Lee, Sam W.
- Abstract
DDR1, discoidin domain receptor 1, belongs to a sub- family of tyrosine kinase receptors with an extracellular domain homologous to Dictyostellium discoideum protein discoidin 1. We showed that DDR1 is a direct p53 transcriptional target, and that DNA damage induced a p53-dependent DDR1 response associated with activation of its tyrosine kinase. We further demonstrated that DDR1 activated the MAPK cascade in a Ras-dependent manner. Whereas levels of p53, phosphoserine-15 p53, p21, ARE and Bcl-XL were increased in response to exogenous overexpression of activated DDR1, dominant-negative DDR1 inhibited irradiation-induced MAPK activation and p53, phosphoserine-15 p53, as welt as induced p21 and DDR1 levels, suggesting that DDR1 functions in a feedforward loop to increase p53 levels and at least some of its effectors. Nonetheless, inhibition of DDR1 function resulted in strikingly increased apoptosis of wild-type p53-containing cells in response to genotoxic stress through a caspase-dependent pathway. These results strongly imply that this p53 response gene must predominately act to alleviate the adverse effects of stress induced by p53 on its target cell.
- Subjects
PROTEIN-tyrosine kinases; TYROSINE; DNA damage; BIOCHEMICAL genetics; GENETIC toxicology; NUCLEIC acids
- Publication
EMBO Journal, 2003, Vol 22, Issue 6, p1289
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1093/emboj/cdg129