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Molecular and Cellular Biology, March 2007, p. 2092-2102, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01514-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Hypoxia-Inducible Factor 2{alpha} N-Terminal and C-Terminal Transactivation Domains Cooperate To Promote Renal Tumorigenesis In Vivo{triangledown} ,{dagger}

Qin Yan,1,2 Steven Bartz,3 Mao Mao,3 Lianjie Li,1,2 and William G. Kaelin Jr.1,2*

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,1 Howard Hughes Medical Institute, Chevy Chase, Maryland 20815,2 Rosetta Inpharmatics, LLC., Seattle, Washington 981093

Received 14 August 2006/ Returned for modification 27 September 2006/ Accepted 19 December 2006

Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor, consisting of an alpha subunit and a beta subunit, that controls cellular responses to hypoxia. HIF{alpha} contains two transcriptional activation domains called the N-terminal transactivation domain (NTAD) and the C-terminal transactivation domain (CTAD). HIF{alpha} is destabilized by prolyl hydroxylation catalyzed by EglN family members. In addition, CTAD function is inhibited by asparagine hydroxylation catalyzed by FIH1. Both hydroxylation reactions are linked to oxygen availability. The von Hippel-Lindau tumor suppressor protein (pVHL) is frequently mutated in kidney cancer and is part of the ubiquitin ligase complex that targets prolyl hydroxylated HIF{alpha} for destruction. Recent studies suggest that HIF2{alpha} plays an especially important role in promoting tumor formation by pVHL-defective renal carcinoma cells among the three HIF{alpha} paralogs. Here we dissected the relative contribution of the two HIF2{alpha} transactivation domains to hypoxic gene activation and renal carcinogenesis and investigated the regulation of the HIF2{alpha} CTAD by FIH1. We found that the HIF2{alpha} NTAD is capable of activating both artificial and naturally occurring HIF-responsive promoters in the absence of the CTAD. Moreover, we found that the HIF2{alpha} CTAD, in contrast to the HIF1{alpha} CTAD, is relatively resistant to the inhibitory effects of FIH1 under normoxic conditions and that, perhaps as a result, both the NTAD and CTAD cooperate to promote renal carcinogenesis in vivo.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115. Phone: (617) 632-3975. Fax: (617) 632-4760. E-mail: william_kaelin{at}dfci.harvard.edu.

{triangledown} Published ahead of print on 12 January 2007.

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

Molecular and Cellular Biology, March 2007, p. 2092-2102, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01514-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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