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Molecular and Cellular Biology, January 2008, p. 93-107, Vol. 28, No. 1
0270-7306/08/$08.00+0 doi:10.1128/MCB.00973-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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Laboratory of Cellular and Molecular Biology, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224,1 Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205,2 Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario K1H 8L1, Canada3
Received 2 June 2007/ Returned for modification 16 July 2007/ Accepted 15 October 2007
The levels of hypoxia-inducible factor 1
(HIF-1
) are tightly controlled. Here, we investigated the posttranscriptional regulation of HIF-1
expression in human cervical carcinoma HeLa cells responding to the hypoxia mimetic CoCl2. Undetectable in untreated cells, HIF-1
levels increased dramatically in CoCl2-treated cells, while HIF-1
mRNA levels were unchanged. HIF-1
translation was potently elevated by CoCl2 treatment, as determined by de novo translation analysis and by monitoring the polysomal association of HIF-1
mRNA. An internal ribosome entry site in the HIF-1
5' untranslated region (UTR) was found to enhance translation constitutively, but it did not further induce translation in response to CoCl2 treatment. Instead, we postulated that RNA-binding proteins HuR and PTB, previously shown to bind HIF-1
mRNA, participated in its translational upregulation after CoCl2 treatment. Indeed, both RNA-binding proteins were found to bind HIF-1
mRNA in a CoCl2-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-1
3'UTR, while HuR associated principally with the 5'UTR. Lowering PTB expression or HuR expression using RNA interference reduced HIF-1
translation and expression levels but not HIF-1
mRNA abundance. Conversely, HIF-1
expression and translation in response to CoCl2 were markedly elevated after HuR overexpression. We propose that HuR and PTB jointly upregulate HIF-1
translation in response to CoCl2.
Published ahead of print on 29 October 2007.
Supplemental material for this article may be found at http://mcb.asm.org/.
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