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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,{dagger} 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. Ratcliffe1*

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 {alpha} subunits (HIF-1{alpha} and HIF-2{alpha}), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1{alpha} and HIF-2{alpha} in RCC and non-RCC cells. We demonstrate common patterns of HIF-{alpha} isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types. We also show that HIF-{alpha} isoforms display unexpected suppressive interactions in RCC cells, with enhanced expression of HIF-2{alpha} suppressing HIF-1{alpha} 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{alpha} and that the proapoptotic gene encoding BNip3 responds positively to HIF-1{alpha} and negatively to HIF-2{alpha}, indicating that HIF-1{alpha} and HIF-2{alpha} have contrasting properties in the biology of RCC. In keeping with this, HIF-{alpha} isoform-specific transcriptional selectivity was matched by differential effects on the growth of RCC as tumor xenografts, with HIF-1{alpha} retarding and HIF-2{alpha} 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.

* Corresponding author. Mailing address: The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom. Phone: 44 (0)1865-857-621. Fax: 44 (0)1865-857-623. E-mail: pjr{at}well.ox.ac.uk.

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

Molecular and Cellular Biology, July 2005, p. 5675-5686, Vol. 25, No. 13
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.13.5675-5686.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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