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J. Biol. Chem., Vol. 279, Issue 16, 16128-16135, April 16, 2004

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Aryl Hydrocarbon Nuclear Translocator (ARNT) Promotes Oxygen-independent Stabilization of Hypoxia-inducible Factor-1 by Modulating an Hsp90-dependent Regulatory Pathway^*

Jennifer S. Isaacs, Yun-Jin Jung, and Len Neckers

From the Urologic Oncology Branch, Center for Cancer Research, NCI, National Institutes of Health, Rockville, Maryland 20850

Hypoxia-inducible factor-1 (HIF-1) is a potent cellular survival factor contributing to tumorigenesis in a broad range of cancers. The functional transcription factor exists as a heterodimeric complex consisting of HIF-1 and the aryl hydrocarbon receptor nuclear translocator (ARNT). Association of HIF-1 with ARNT is required for its activity; however, no other role has been ascribed to this interaction. We demonstrated previously that pharmacologic inhibition of Hsp90 by geldanamycin (GA) impairs HIF transcription and promotes VHL (Von Hippel-Lindau)-independent degradation of the protein, thus implicating Hsp90 as an essential interacting partner for HIF. In this study, we further explore the physiological role for Hsp90 in HIF function. We establish that the PAS (Per-ARNT-Sim) domain of HIF is required both to promote association with Hsp90 and confer sensitivity to GA. Coincidentally, this domain also associates with ARNT. Overexpression of ARNT in a VHL-deficient background resulted in substantially increased HIF-1 protein concomitant with increased protein stability. Conversely, down-regulation of endogenous ARNT protein by RNA interference decreased the steady-state HIF protein. ARNT-mediated stabilization of HIF is specific for the Hsp90-dependent pathway, as ARNT was unable to protect HIF from VHL-mediated degradation. We establish that the ability of ARNT to up-regulate HIF and diminish HIF sensitivity to GA is due to its ability to compete for the Hsp90 binding site on HIF. These data elucidate novel functions for ARNT and Hsp90 in regulating HIF function and further illustrate that cofactor association may significantly impact upon the sensitivity of Hsp90 clients to chaperone inhibitors.

Received for publication, December 5, 2003 , and in revised form, February 4, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Urologic Oncology Branch, NCI, National Institutes of Health, 9610 Medical Center Dr., KWC Ste. 300, Rockville, MD 20850. Tel.: 301-496-5137; Fax: 301-402-4422; E-mail: isaacsj{at}mail.nih.gov. To whom correspondence may be addressed: Urologic Oncology Branch, NCI, National Institutes of Health, 9610 Medical Center Dr., KWC Ste. 300, Rockville, MD 20850. Tel.: 301-496-5899; Fax: 301-402-4422; E-mail: len{at}helix.nih.gov.

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