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J. Biol. Chem., Vol. 275, Issue 36, 28039-28044, September 8, 2000
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From the Laboratory of Molecular Carcinogenesis and Center for
Biomedical Genetics, Leiden University Medical Center, P.O. Box 9503, 2300 RA Leiden, The Netherlands
The Mdm2 protein is a key regulator of p53
activity and stability. Upon binding, Mdm2 inhibits the transcription
regulatory activity of p53 and promotes its rapid degradation. In this
study we investigated the effect of the human Mdm2 homologue Hdmx on p53 stability. We found that Hdmx does not target p53 for degradation, although, like Mdm2, it inhibits p53-mediated transcription activation. On the contrary, Hdmx was found to counteract the degradation of p53 by
Mdm2, and to stabilize both p53 and Mdm2. The RING finger of Hdmx was
found to be necessary and sufficient for this stabilization, and it
probably involves hetero-oligomerization with the RING finger of Mdm2,
which may lead to inhibition of Mdm2's ubiquitin ligase activity.
However, Hdmx does not relieve the inhibition by Mdm2 of transcription
activation by p53, probably due to the formation of a trimeric complex
consisting of Hdmx, Mdm2, and p53. We propose a model in which Hdmx
secures a pool of largely inactive p53, which, upon the induction of
stress, can be quickly activated.
Hdmx Stabilizes Mdm2 and p53*
,,
*
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.
Supported by the Dutch Cancer Society.
§
To whom correspondence should be addressed. Tel.: 31-71-5276136;
Fax: 31-71-5276284; E-mail: a.g.jochemsen@lumc.nl.
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