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Molecular and Cellular Biology, July 2003, p. 4959-4971, Vol. 23, No. 14
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.14.4959-4971.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Hypoxia-Induced Gene Expression Occurs Solely through the Action of Hypoxia-Inducible Factor 1{alpha} (HIF-1{alpha}): Role of Cytoplasmic Trapping of HIF-2{alpha}

Sang-ki Park,1 Agnes M. Dadak,1,{dagger} Volker H. Haase,2 Lucrezia Fontana,3 Amato J. Giaccia,3 and Randall S. Johnson1*

Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093-0366,1 Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6144,2 Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, California 94303-51523

Received 7 November 2002/ Returned for modification 20 January 2003/ Accepted 18 April 2003

The hypoxia-inducible factors 1{alpha} (HIF-1{alpha}) and 2{alpha} (HIF-2{alpha}) have extensive structural homology and have been identified as key transcription factors responsible for gene expression in response to hypoxia. They play critical roles not only in normal development, but also in tumor progression. Here we report on the differential regulation of protein expression and transcriptional activity of HIF-1{alpha} and -2{alpha} by hypoxia in immortalized mouse embryo fibroblasts (MEFs). We show that oxygen-dependent protein degradation is restricted to HIF-1{alpha}, as HIF-2{alpha} protein is detected in MEFs regardless of oxygenation and is localized primarily to the cytoplasm. Endogenous HIF-2{alpha} remained transcriptionally inactive under hypoxic conditions; however, ectopically overexpressed HIF-2{alpha} translocated into the nucleus and could stimulate expression of hypoxia-inducible genes. We show that the factor inhibiting HIF-1 can selectively inhibit the transcriptional activity of HIF-1{alpha} but has no effect on HIF-2{alpha}-mediated transcription in MEFs. We propose that HIF-2{alpha} is not a redundant transcription factor of HIF-1{alpha} for hypoxia-induced gene expression and show evidence that there is a cell type-specific modulator(s) that enables selective activation of HIF-1{alpha} but not HIF-2{alpha} in response to low-oxygen stress.

* Corresponding author. Mailing address: Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0366. Phone: (858) 822-0509. Fax: (858) 822-5833. E-mail: rjohnson{at}biomail.ucsd.edu.

{dagger} Present address: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, A-1210 Vienna, Austria.

Molecular and Cellular Biology, July 2003, p. 4959-4971, Vol. 23, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.14.4959-4971.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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