Studies of hypoxia response and regulation of hypoxia-inducible factor HIF-1 in Caenorhabditis elegans

Abstract

The human hypoxia-inducible transcription factor HIF-1 is a critical regulator of cellular and systemic responses to low oxygen levels. When oxygen levels are high, the HIFla subunit is hydroxylated and is targeted for degradation by the von Hippel-Lindau tumor suppressor protein (pVHL). This regulatory pathway is evolutionary conserved, and the Caenorhabditis elegans hif-1 and vhl-1 genes encode homologs of the HEF-la subunit and VHL. To understand and describe more fully the molecular basis for hypoxia response in this important genetic model system, we compared hypoxia-induced changes in mRNA expression in wild-type, hif-1 -deficient, and vhl-1 -deficient C. elegans using whole genome microarrays. These studies identified 110 hypoxia-regulated gene expression changes, 63 of which require hif-1 function. Mutation of vhl-1 abrogates most hif-1-dependent changes in