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J. Biol. Chem., Vol. 275, Issue 47, 37296-37302, November 24, 2000
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From the Ludwig Institute for Cancer Research, Imperial College of
Science, Technology and Medicine at St. Mary's Campus, Norfolk Place,
London, W2 1PG United Kingdom
The ability of Mdm2 to inhibit the activities of
a C-terminal truncated p53 mutant, p53-
Mdm2 Inhibits the Apoptotic Function of p53 Mainly by
Targeting It for Degradation*
30, which can bind
Mdm2 but is resistant to Mdm2-mediated protein degradation was
investigated. The inhibitory function of an Mdm2 mutant,
Mdm2-(222-437), which can bind p53 but is defective in targeting
p53 for degradation was also studied. We have demonstrated that
targeting p53 for degradation is the most effective way for Mdm2 to
inhibit the apoptotic function of p53. However, we have also shown that
Mdm2 can inhibit the transactivation function of p53 without targeting
it for degradation, although Mdm2 releases the transrepression ability
of p53 mainly by targeting it for degradation. The ability of Mdm2 to
inhibit the apoptotic function of p53 was linked to its ability to
inhibit the transrepression but not the transactivation function of
p53. Furthermore, we have demonstrated that the transrepression
function of p53 was specific to p53-induced apoptosis and was not
simply a result of cell death.
*
This work was supported by Ludwig Inst. for Cancer Research.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 44-207-563-7710;
Fax: 44-207-724-8586; E-mail: x.lu@ic.ac.uk.
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