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.
Li
June
J
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Zhang
Xiaoling
X
Sejas
Daniel P
DP
Bagby
Grover C
GC
Pang
Qishen
Q
D017209:Apoptosis; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000502:physiology*; D056489:Nucleoplasmins; D010750:Phosphoproteins / Q000096:biosynthesis / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D020218:Response Elements; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D056489:Nucleoplasmins; D010750:Phosphoproteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53