Hypoxia-induced nucleophosmin protects cell death through inhibition of p53.

Nucleophosmin (NPM) is a multifunctional protein that is overexpressed in actively proliferating cells and cancer cells. Here we report that this proliferation-promoting protein is strongly induced in response to hypoxia in human normal and cancer cells. Up-regulation of NPM is hypoxia-inducible factor-1 (HIF-1)-dependent. The NPM promoter encodes a functional HIF-1-responsive ...
element that can be activated by hypoxia or forced expression of HIF-1alpha. Suppression of NPM expression by small interfering RNA targeting NPM increases hypoxia-induced apoptosis, whereas overexpression of NPM protects against hypoxic cell death of wild-type but not p53-null cells. Moreover, NPM inhibits hypoxia-induced p53 phosphorylation at Ser-15 and interacts with p53 in hypoxic cells. Thus, this study not only demonstrates hypoxia regulation of a proliferation-promoting protein but also suggests that hypoxia-driven cancer progression may require increased expression of NPM to suppress p53 activation and maintain cell survival.
Mesh Terms:
Apoptosis, Cell Line, Tumor, Cells, Cultured, DNA-Binding Proteins, Humans, Hypoxia, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Neoplasms, Nuclear Proteins, Nucleoplasmins, Phosphoproteins, Phosphorylation, Promoter Regions, Genetic, Response Elements, Transcription Factors, Transcription, Genetic, Tumor Suppressor Protein p53, Up-Regulation
J. Biol. Chem.
Date: Oct. 01, 2004
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