Regulation of the hypoxia-inducible transcription factor HIF-1 by reactive oxygen species in smooth muscle cells.

Abstract

Hypoxia is able to activate the expression of a number of genes that are important for the cell to adapt to low oxygen conditions such as erythropoietin, vascular endothelial growth factor (VEGF) or plasminogen activator inhibitor-1 (PAI-1). The major transcription factor involved in the gene induction by hypoxia is the hypoxia-inducible factor-1 (HIF-1) (Semenza et al. 2001) which consists of two subunits, HIF-1 a and HIF-s also known as ARNT. While the ARNT protein is readily found in the cell, the HIF-1 a protein is undetectable under normoxic conditions. In fact, under normal oxygen conditions, this protein is modified by prolyl and asparaginyl hydroxylation, ubiquitinylated and degradated by the proteasome. During hypoxia, hydroxylase activity is reduced, thus allowing HIF-1 a protein levels to increase (Kaelin, 2002). The HIF-1 a protein can then translocate to the nucleus, interact with the ARNT subunit, bind to specific DNA binding sites named hypoxia response elements (HRE) and finally induce transcription of the target genes.