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J. Biol. Chem., Vol. 276, Issue 21, 18497-18506, May 25, 2001
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From The wild type p53 tumor suppressor protein is
rapidly degraded in normal cells by MDM2, the ubiquitin ligase that
serves as the key regulator of p53 function by modulating protein
stability. Cellular exposure to genotoxic stress triggers the
stabilization of p53 by multiple pathways that converge upon
interference with MDM2 function. In this study, we first investigated
the ability of HDM2 (MDM2 human homologue) to degrade endogenous p53 in
neuroblastoma (NB). Although the p53 protein in NB has been reported to
be constitutively stabilized, we find that HDM2 in NB is functional and
facilitates the rapid turnover of p53 in nonstressed cells via the
proteasome pathway. Second, we examined the relationship between p53
and HDM2 in the adriamycin-mediated stabilization of p53 in NB. We demonstrate that while p53 stabilization depends neither upon the
phosphorylation of specific N-terminal sites nor upon dissociation from
HDM2, it requires inactivation of functional HDM2. In support of this
notion, p53 stabilization following adriamycin resulted in an
inhibition of both p53 ubiquitination and HDM2 ligase activity. Taken
together, these data implicate a requirement for enzymatic inactivation
of HDM2 as a novel mechanism for p53 stabilization in the DNA damage
response pathway.
Requirement for HDM2 Activity in the Rapid Degradation
of p53 in Neuroblastoma*
,¶
Tumor Cell Biology Section, Medicine
Branch, NCI, National Institutes of Health, Rockville, Maryland 20850 and the § Laboratory of Cell Biology, NCI, National
Institutes of Health, Bethesda, Maryland 20892-1152
*
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.
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