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

Stefanie Galbán, Yuki Kuwano, Rudolf Pullmann, Jennifer L. Martindale, Ho Kim Hyeon, Ashish Lal, Kotb Abdelmohsen, Xiaoling Yang, Youngjun Dang, Jun O. Liu, Stephen M. Lewis, Martin Holcik, Myriam Gorospe

Research output: Contribution to journalArticle

Abstract

The levels of hypoxia-inducible factor 1α (HIF-1α) are tightly controlled. Here, we investigated the post-transcriptional regulation of HIF-1α expression in human cervical carcinoma HeLa cells responding to the hypoxia mimetic CoCl2. Undetectable in untreated cells, HIF-1α levels increased dramatically in CoCl2-treated cells, while HIF-1α mRNA levels were unchanged. HIF-1α translation was potently elevated by CoCl2 treatment, as determined by de novo translation analysis and by monitoring the polysomal association of HIF-1α mRNA. An internal ribosome entry site in the HIF-1α 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-1α mRNA, participated in its translational upregulation after CoCl2 treatment. Indeed, both RNA-binding proteins were found to bind HIF-1α mRNA in a CoCl2-inducible manner as assessed by immunoprecipitation of endogenous ribonucleo-protein complexes. Using a chimeric reporter, polypyrimidine tract-binding protein (PTB) was found to bind the HIF-1α 3′UTR, while HuR associated principally with the 5′UTR. Lowering PTB expression or HuR expression using RNA interference reduced HIF-1α translation and expression levels but not HIF-1α mRNA abundance. Conversely, HIF-1α expression and translation in response to CoCl2 were markedly elevated after HuR overexpression. We propose that HuR and PTB jointly upregulate HIF-1α translation in response to CoCl2.

Original languageEnglish (US)
Pages (from-to)93-107
Number of pages15
JournalMolecular and cellular biology
Volume28
Issue number1
DOIs
StatePublished - Jan 1 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Galbán, S., Kuwano, Y., Pullmann, R., Martindale, J. L., Hyeon, H. K., Lal, A., Abdelmohsen, K., Yang, X., Dang, Y., Liu, J. O., Lewis, S. M., Holcik, M., & Gorospe, M. (2008). RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1α. Molecular and cellular biology, 28(1), 93-107. https://doi.org/10.1128/MCB.00973-07