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Molecular and Cellular Biology, June 2006, p. 4628-4641, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.02236-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cell-Type-Specific Regulation of Degradation of Hypoxia-Inducible Factor 1{alpha}: Role of Subcellular Compartmentalization

Xiaowei Zheng,1,3 Jorge L. Ruas,1 Renhai Cao,2 Florian A. Salomons,1 Yihai Cao,2 Lorenz Poellinger,1* and Teresa Pereira1

Department of Cell and Molecular Biology,1 Microbiology and Tumor Biology Center, Karolinska Institutet, S-171 77 Stockholm, Sweden,2 Department of Cardiology, First Affiliated Hospital, China Medical University, Shenyang 110001, People's Republic of China3

Received 19 November 2005/ Returned for modification 15 December 2005/ Accepted 24 March 2006

The hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) is a transcription factor that mediates adaptive cellular responses to decreased oxygen availability (hypoxia). At normoxia, HIF-1{alpha} is targeted by the von Hippel-Lindau tumor suppressor protein (pVHL) for degradation by the ubiquitin-proteasome pathway. In the present study we have observed distinct cell-type-specific differences in the ability of various tested pVHL-interacting subfragments to stabilize HIF-1{alpha} and unmask its function at normoxia. These properties correlated with differences in subcellular compartmentalization and degradation of HIF-1{alpha}. We observed that the absence or presence of nuclear localization or export signals differently affected the ability of a minimal HIF-1{alpha} peptide spanning residues 559 to 573 of mouse HIF-1{alpha} to stabilize endogenous HIF{alpha} and induce HIF-driven reporter gene activity in two different cell types (primary mouse endothelial and HepG2 hepatoma cells). Degradation of HIF-1{alpha} occurred mainly in the cytoplasm of HepG2 cells, whereas it occurs with equal efficiency in nuclear and cytoplasmic compartments of primary endothelial cells. Consistent with these observations, green fluorescent protein-HIF-1{alpha} is differently distributed during hypoxia and reoxygenation in hepatoma and endothelial cells. Consequently, we propose that differential compartmentalization of degradation of HIF-1{alpha} and the subcellular distribution of HIF-1{alpha} may account for cell-type-specific differences in stabilizing HIF-1{alpha} protein levels under hypoxic conditions.

* Corresponding author. Mailing address: Department of Cell and Molecular Biology, Karolinska Institutet, S-171 77 Stockholm, Sweden. Phone: 46 8 5248 7330. Fax: 46 8 34 88 19. E-mail: lorenz.poellinger{at}cmb.ki.se.

Molecular and Cellular Biology, June 2006, p. 4628-4641, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.02236-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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