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

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 (HIF-1) is a transcription factor that mediates adaptive cellular responses to decreased oxygen availability (hypoxia). At normoxia, HIF-1 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 and unmask its function at normoxia. These properties correlated with differences in subcellular compartmentalization and degradation of HIF-1. We observed that the absence or presence of nuclear localization or export signals differently affected the ability of a minimal HIF-1 peptide spanning residues 559 to 573 of mouse HIF-1 to stabilize endogenous HIF and induce HIF-driven reporter gene activity in two different cell types (primary mouse endothelial and HepG2 hepatoma cells). Degradation of HIF-1 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 is differently distributed during hypoxia and reoxygenation in hepatoma and endothelial cells. Consequently, we propose that differential compartmentalization of degradation of HIF-1 and the subcellular distribution of HIF-1 may account for cell-type-specific differences in stabilizing HIF-1 protein levels under hypoxic conditions.

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