Stimulation of p53-dependent Transcription by the Growth Suppressor, c-Abl
Annual rept 1 Jun 98-31 May 99
CALIFORNIA UNIV RIVERSIDE
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Growth suppressor c-Abl interacts with p53 in response to DNA damage and over-expression of c-Abl leads to G1 growth arrest in a p53-dependent manner. Here, we show that c-Abl binds directly to the carboxyl terminal regulatory domain of p53 and that this interaction requires tetramerization of p53. Importantly, we demonstrate that c-Abl stimulates the DNA-binding activity of wild-type p53 but not of a carboxyl-terminally truncated p53 p53 delta 363C, and furthermore, a deletion mutant of c-Abl that does not bind to p53 is also incapable of activating p53 DNA-binding, suggesting that the binding to the p53 carboxyl terminus is necessary for c-Abl stimulation. To investigate the mechanism for this activation, we have also shown that c-Abl stabilizes the p53-DNA complex. Interestingly, the stimulation of p53 DNA-binding by c-Abl does not require its tyrosine kinase activity, indicating a new function for c-Abl. Together, these observations provide evidence for a role of c-Abl as a growth suppressor protein in activation of p53 DNA-binding via the carboxyl terminal regulatory domain and tetramerization.
- Medicine and Medical Research