This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Galbán, S.
Right arrow Articles by Gorospe, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Galbán, S.
Right arrow Articles by Gorospe, M.

 Previous Article  |  Next Article 

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.

RNA-Binding Proteins HuR and PTB Promote the Translation of Hypoxia-Inducible Factor 1{alpha}{triangledown} ,{dagger}

Stefanie Galbán,1 Yuki Kuwano,1 Rudolf Pullmann Jr.,1 Jennifer L. Martindale,1 Hyeon Ho Kim,1 Ashish Lal,1 Kotb Abdelmohsen,1 Xiaoling Yang,1 Youngjun Dang,2 Jun O. Liu,2 Stephen M. Lewis,3 Martin Holcik,3 and Myriam Gorospe1*

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{alpha} (HIF-1{alpha}) are tightly controlled. Here, we investigated the posttranscriptional regulation of HIF-1{alpha} expression in human cervical carcinoma HeLa cells responding to the hypoxia mimetic CoCl2. Undetectable in untreated cells, HIF-1{alpha} levels increased dramatically in CoCl2-treated cells, while HIF-1{alpha} mRNA levels were unchanged. HIF-1{alpha} translation was potently elevated by CoCl2 treatment, as determined by de novo translation analysis and by monitoring the polysomal association of HIF-1{alpha} mRNA. An internal ribosome entry site in the HIF-1{alpha} 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{alpha} mRNA, participated in its translational upregulation after CoCl2 treatment. Indeed, both RNA-binding proteins were found to bind HIF-1{alpha} 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{alpha} 3'UTR, while HuR associated principally with the 5'UTR. Lowering PTB expression or HuR expression using RNA interference reduced HIF-1{alpha} translation and expression levels but not HIF-1{alpha} mRNA abundance. Conversely, HIF-1{alpha} expression and translation in response to CoCl2 were markedly elevated after HuR overexpression. We propose that HuR and PTB jointly upregulate HIF-1{alpha} translation in response to CoCl2.

* Corresponding author. Mailing address: LCMB, NIA, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224. Phone: (410) 558-8443. Fax: (410) 558-8386. E-mail: myriam-gorospe{at}nih.gov

{triangledown} Published ahead of print on 29 October 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

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.



This article has been cited by other articles:

  • Kuwano, Y., Pullmann, R. Jr., Marasa, B. S., Abdelmohsen, K., Lee, E. K., Yang, X., Martindale, J. L., Zhan, M., Gorospe, M. (2009). NF90 selectively represses the translation of target mRNAs bearing an AU-rich signature motif. Nucleic Acids Res 0: gkp861v1-gkp861 [Abstract] [Full Text]  
  • Babic, I., Sharma, S., Black, D. L. (2009). A Role for Polypyrimidine Tract Binding Protein in the Establishment of Focal Adhesions. Mol. Cell. Biol. 29: 5564-5577 [Abstract] [Full Text]  
  • Zhang, X., Zou, T., Rao, J. N., Liu, L., Xiao, L., Wang, P.-Y., Cui, Y.-H., Gorospe, M., Wang, J.-Y. (2009). Stabilization of XIAP mRNA through the RNA binding protein HuR regulated by cellular polyamines. Nucleic Acids Res 0: gkp755v1-gkp755 [Abstract] [Full Text]  
  • Ayupova, D. A., Singh, M., Leonard, E. C., Basile, D. P., Lee, B. S. (2009). Expression of the RNA-stabilizing protein HuR in ischemia-reperfusion injury of rat kidney. Am. J. Physiol. Renal Physiol. 297: F95-F105 [Abstract] [Full Text]  
  • Kuwano, Y., Rabinovic, A., Srikantan, S., Gorospe, M., Demple, B. (2009). Analysis of Nitric Oxide-Stabilized mRNAs in Human Fibroblasts Reveals HuR-Dependent Heme Oxygenase 1 Upregulation. Mol. Cell. Biol. 29: 2622-2635 [Abstract] [Full Text]  
  • Gomes, E. M., Rodrigues, M. S., Phadke, A. P., Butcher, L. D., Starling, C., Chen, S., Chang, D., Hernandez-Alcoceba, R., Newman, J. T., Stone, M. J., Tong, A. W. (2009). Antitumor Activity of an Oncolytic Adenoviral-CD40 Ligand (CD154) Transgene Construct in Human Breast Cancer Cells. Clin. Cancer Res. 15: 1317-1325 [Abstract] [Full Text]  
  • Besse, F., Lopez de Quinto, S., Marchand, V., Trucco, A., Ephrussi, A. (2009). Drosophila PTB promotes formation of high-order RNP particles and represses oskar translation. Genes Dev. 23: 195-207 [Abstract] [Full Text]  
  • Ham, B.-K., Brandom, J. L., Xoconostle-Cazares, B., Ringgold, V., Lough, T. J., Lucas, W. J. (2009). A Polypyrimidine Tract Binding Protein, Pumpkin RBP50, Forms the Basis of a Phloem-Mobile Ribonucleoprotein Complex. Plant Cell 21: 197-215 [Abstract] [Full Text]  
  • Abdelmohsen, K., Srikantan, S., Kuwano, Y., Gorospe, M. (2008). miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels. Proc. Natl. Acad. Sci. USA 105: 20297-20302 [Abstract] [Full Text]  
  • Young, R. M., Wang, S.-J., Gordan, J. D., Ji, X., Liebhaber, S. A., Simon, M. C. (2008). Hypoxia-mediated Selective mRNA Translation by an Internal Ribosome Entry Site-independent Mechanism. J. Biol. Chem. 283: 16309-16319 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»