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Molecular and Cellular Biology, October 2003, p. 7083-7095, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7083-7095.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Influence of the RNA-Binding Protein HuR in pVHL-Regulated p53 Expression in Renal Carcinoma Cells

Stefanie Galbán,1 Jennifer L. Martindale,1 Krystyna Mazan-Mamczarz,1 Isabel López de Silanes,1 Jinshui Fan,1 Wengong Wang,1 Jochen Decker,2 and Myriam Gorospe1*

Laboratory of Cellular and Molecular Biology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224,1 Bioscientia Institute, 55128 Ingelheim, Germany2

Received 6 June 2003/ Returned for modification 3 July 2003/ Accepted 9 July 2003

A recent analysis of gene expression in renal cell carcinoma cells led to the identification of mRNAs whose translation was dependent on the presence of the von Hippel-Lindau (VHL) tumor suppressor gene product, pVHL. Here, we investigate the finding that pVHL-expressing RCC cells (VHL+) exhibited elevated levels of polysome-associated p53 mRNA and increased p53 protein levels compared with VHL-defective (VHL-) cells. Our findings indicate that p53 translation is specifically heightened in VHL+ cells, given that (i) p53 mRNA abundance in VHL+ and VHL- cells was comparable, (ii) p53 degradation did not significantly influence p53 expression, and (iii) p53 synthesis was markedly induced in VHL+ cells. Electrophoretic mobility shift and immunoprecipitation assays to detect endogenous and radiolabeled p53 transcripts revealed that the RNA-binding protein HuR, previously shown to regulate mRNA turnover and translation, was capable of binding to the 3' untranslated region of the p53 mRNA in a VHL-dependent fashion. Interestingly, while whole-cell levels of HuR in VHL+ and VHL- cells were comparable, HuR was markedly more abundant in the cytoplasmic and polysome-associated fractions of VHL+ cells. In keeping with earlier reports, the elevated cytoplasmic HuR in VHL+ cells was likely due to the reduced AMP-activated kinase activity in these cells. Demonstration that HuR indeed contributed to the increased expression of p53 in VHL+ cells was obtained through use of RNA interference, which effectively reduced HuR expression and in turn caused marked decreases in p53 translation and p53 abundance. Taken together, our findings support a role for pVHL in elevating p53 expression, implicate HuR in enhancing VHL-mediated p53 translation, and suggest that VHL-mediated p53 upregulation may contribute to pVHL's tumor suppressive functions in renal cell carcinoma.

* 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, October 2003, p. 7083-7095, Vol. 23, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.20.7083-7095.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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