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Molecular and Cellular Biology, July 2005, p. 5675-5686, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5675-5686.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Contrasting Properties of Hypoxia-Inducible Factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-Associated Renal Cell Carcinoma

Raju R. Raval,^1, Kah Weng Lau,¹ Maxine G. B. Tran,² Heidi M. Sowter,³ Stefano J. Mandriota,¹ Ji-Liang Li,³ Christopher W. Pugh,¹ Patrick H. Maxwell,² Adrian L. Harris,³ and Peter J. Ratcliffe^1*

The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN,¹ Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU,³ Renal Section, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom²

Received 29 November 2004/ Returned for modification 10 December 2004/ Accepted 27 March 2005

Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor subunits (HIF-1 and HIF-2), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1 and HIF-2 in RCC and non-RCC cells. We demonstrate common patterns of HIF- isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types. We also show that HIF- isoforms display unexpected suppressive interactions in RCC cells, with enhanced expression of HIF-2 suppressing HIF-1 and vice-versa. In VHL-defective RCC cells, we demonstrate that the protumorigenic genes encoding cyclin D1, transforming growth factor alpha, and vascular endothelial growth factor respond specifically to HIF-2 and that the proapoptotic gene encoding BNip3 responds positively to HIF-1 and negatively to HIF-2, indicating that HIF-1 and HIF-2 have contrasting properties in the biology of RCC. In keeping with this, HIF- isoform-specific transcriptional selectivity was matched by differential effects on the growth of RCC as tumor xenografts, with HIF-1 retarding and HIF-2 enhancing tumor growth. These findings indicate that therapeutic approaches to targeting of the HIF system, at least in this setting, will need to take account of HIF isoform-specific functions.

Present address: University of Pennsylvania School of Medicine, Philadelphia, PA 19104.

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