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J Biol Chem, Vol. 274, Issue 39, 27474-27480, September 24, 1999
From the Department of Pathology, State University of New York,
Stony Brook, New York 11794
The Mdm2 oncoprotein mediates p53 degradation at
cytoplasmic proteasomes and is the principal regulator for maintaining
low, often undetectable levels of p53 in unstressed cells. However, a
subset of human tumors including neuroblastoma constitutively harbor
high levels of wild type p53 protein localized to the cytoplasm. Here
we show that the abnormal p53 accumulation in such cells is due to a
profound resistance to Mdm2-mediated degradation. Overexpression of
Mdm2 in neuroblastoma (NB)1
cell lines failed to decrease the high steady state levels of endogenous p53. Moreover, exogenous p53, when introduced into these
cells, was also resistant to Mdm2-directed degradation. This resistance
is not due to a lack of Mdm2 expression in NB cells or a lack of
p53-Mdm2 interaction, nor is it due to a deficiency in the
ubiquitination state of p53 or proteasome dysfunction. Instead,
Mdm2-resistant p53 from NB cells is associated with covalent modification of p53 and masking of the modification-sensitive PAb 421 epitope. This system provides evidence for an important level of
regulation of Mdm2-directed p53 destruction in vivo that is
linked to p53 modification.
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