Research article summary (published 27 Oct 2007):

RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1alpha.

Full 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).

Author information

Author/s: Galbán, Stefanie (S); Kuwano, Yuki (Y); Pullmann, Rudolf (R); Martindale, Jennifer L (JL); Kim, Hyeon Ho (HH); Lal, Ashish (A); Abdelmohsen, Kotb (K); Yang, Xiaoling (X); Dang, Youngjun (Y); Liu, Jun O (JO); Lewis, Stephen M (SM); Holcik, Martin (M); Gorospe, Myriam (M);

Affiliation: LCMB, NIA, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224, USA.

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Intramural

Journal: Molecular and cellular biology (Mol Cell Biol), published in United States. (Language: eng)

Reference: 2008-Jan; vol 28 (issue 1) : pp 93-107

Dates: Created 2007/12/19; Completed 2008/01/11; Revised 2008/11/20;

PMID: 17967866, status: MEDLINE (last retrieved date: 2/18/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Antigens, Surface - genetics; metabolism Cell Hypoxia - drug effects Cell Line, Tumor Cobalt - pharmacology Gene Expression Regulation - drug effects Humans Hypoxia-Inducible Factor 1, alpha Subunit - genetics; metabolism Polypyrimidine Tract-Binding Protein - genetics; metabolism

Protein Binding Protein Biosynthesis - drug effects Protein Transport RNA Interference RNA, Messenger - genetics RNA-Binding Proteins - genetics; metabolism Ribosomes - genetics; metabolism Transcription, Genetic - genetics

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Antigens, Surface (0) ; ELAV-like protein 1 (0) ; Hypoxia-Inducible Factor 1, alpha Subunit (0) ; RNA, Messenger (0) ; RNA-Binding Proteins (0) ; Polypyrimidine Tract-Binding Protein (139076-35-0) ; Cobalt (7440-48-4) ; cobaltous chloride (7646-79-9)

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