PMID:17967866

Citation	Galbán, S, Kuwano, Y, Pullmann, R Jr, Martindale, JL, Kim, HH, Lal, A, Abdelmohsen, K, Yang, X, Dang, Y, Liu, JO, Lewis, SM, Holcik, M and Gorospe, M (2008) RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1alpha. Mol. Cell. Biol. 28:93-107
Abstract	The levels of hypoxia-inducible factor 1alpha (HIF-1alpha) are tightly controlled. Here, we investigated the posttranscriptional regulation of HIF-1alpha expression in human cervical carcinoma HeLa cells responding to the hypoxia mimetic CoCl(2). Undetectable in untreated cells, HIF-1alpha levels increased dramatically in CoCl(2)-treated cells, while HIF-1alpha mRNA levels were unchanged. HIF-1alpha translation was potently elevated by CoCl(2) treatment, as determined by de novo translation analysis and by monitoring the polysomal association of HIF-1alpha mRNA. An internal ribosome entry site in the HIF-1alpha 5' untranslated region (UTR) was found to enhance translation constitutively, but it did not further induce translation in response to CoCl(2) treatment. Instead, we postulated that RNA-binding proteins HuR and PTB, previously shown to bind HIF-1alpha mRNA, participated in its translational upregulation after CoCl(2) treatment. Indeed, both RNA-binding proteins were found to bind HIF-1alpha mRNA in a CoCl(2)-inducible manner as assessed by immunoprecipitation of endogenous ribonucleoprotein complexes. Using a chimeric reporter, polypyrimidine tract-binding protein (PTB) was found to bind the HIF-1alpha 3'UTR, while HuR associated principally with the 5'UTR. Lowering PTB expression or HuR expression using RNA interference reduced HIF-1alpha translation and expression levels but not HIF-1alpha mRNA abundance. Conversely, HIF-1alpha expression and translation in response to CoCl(2) were markedly elevated after HuR overexpression. We propose that HuR and PTB jointly upregulate HIF-1alpha translation in response to CoCl(2).
Links	PubMed PMC2223304 Online version:10.1128/MCB.00973-07
Keywords	Antigens, Surface/genetics; Antigens, Surface/metabolism; Cell Hypoxia/drug effects; Cell Line, Tumor; Cobalt/pharmacology; Gene Expression Regulation/drug effects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Polypyrimidine Tract-Binding Protein/genetics; Polypyrimidine Tract-Binding Protein/metabolism; Protein Binding; Protein Biosynthesis/drug effects; Protein Transport; RNA Interference; RNA, Messenger/genetics; RNA-Binding Proteins/genetics; RNA-Binding Proteins/metabolism; Ribosomes/genetics; Ribosomes/metabolism; Transcription, Genetic/genetics
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