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Molecular and Cellular Biology, April 2003, p. 2316-2328, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2316-2328.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

von Hippel-Lindau Protein-Mediated Repression of Tumor Necrosis Factor Alpha Translation Revealed through Use of cDNA Arrays

Stefanie Galbán,1 Jinshui Fan,1 Jennifer L. Martindale,1 Chris Cheadle,2 Bryan Hoffman,3 Michael P. Woods,3 Gretchen Temeles,3 Jürgen Brieger,4 Jochen Decker,5 and Myriam Gorospe1*

Laboratory of Cellular and Molecular Biology,1 DNA Array Unit, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224,2 Message Pharmaceuticals, Inc., Malvern, Pennsylvania 19355,3 Department of Otorhinolaryngology, School of Medicine, Johannes Gutenberg University, 55101 Mainz,4 Bioscientia Institute, 55128 Ingelheim, Germany5

Received 30 October 2002/ Returned for modification 10 December 2002/ Accepted 10 January 2003

Based on evidence that the von Hippel-Lindau (VHL) tumor suppressor protein is associated with polysomes and interacts with translation regulatory factors, we set out to investigate the potential influence of pVHL on protein translation. To this end, renal cell carcinoma (RCC) cells that either lacked pVHL or expressed pVHL through stable transfection were used to prepare RNA from cytosolic (unbound) and polysome-bound fractions. Hybridization of cDNA arrays using RNA from each fraction revealed a subset of transcripts whose abundance in polysomes decreased when pVHL function was restored. The tumor necrosis factor alpha (TNF-{alpha}) mRNA was identified as one of the transcripts that preferentially associated with polysomes in pVHL-deficient cells. Additional evidence that the TNF-{alpha} mRNA was a target of translational repression by pVHL was obtained from reporter gene assays, which further revealed that pVHL's inhibitory influence on protein synthesis occurred through the TNF-{alpha} 3'-untranslated region. Our findings uncover a novel function for the pVHL tumor suppressor protein as regulator of protein translation.

* Corresponding author. Mailing address: Box 12, LCMB, GRC, NIA-IRP, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224. Phone: (410) 558-8443. Fax: (410) 558-8386. E-mail: myriam-gorospe{at}nih.gov.

Molecular and Cellular Biology, April 2003, p. 2316-2328, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2316-2328.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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