Molecular and Cellular Biology, February 2000, p. 741-748, Vol. 20, No. 3
Department of Biochemistry, University of
California, Riverside, California 92521
Received 28 June 1999/Returned for modification 29 July
1999/Accepted 21 October 1999
The carboxyl terminus of p53 is a target of a variety of signals
for regulation of p53 DNA binding. Growth suppressor c-Abl interacts
with p53 in response to DNA damage and overexpression 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
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Stimulation of p53 DNA Binding by c-Abl Requires
the p53 C Terminus and Tetramerization
363C). A deletion mutant of c-Abl that does not bind to p53
is also incapable of activating p53 DNA binding. These data suggest
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. These results led
us to hypothesize that the interaction of c-Abl with the C terminus of
p53 may stabilize the p53 tetrameric conformation, resulting in a more
stable p53-DNA complex. Interestingly, the stimulation of p53
DNA-binding by c-Abl does not require its tyrosine kinase activity,
indicating a kinase-independent function for c-Abl. Together, these
results suggest a detailed mechanism by which c-Abl activates p53
DNA-binding via the carboxyl-terminal regulatory domain and tetramerization.
*
Corresponding author. Mailing address: Department of
Biochemistry, University of California, Riverside, CA 92521. Phone:
(909) 787-4350. Fax: (909) 787-4434. E-mail:
xuan.liu{at}ucr.edu.
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