Roles of the HIF-1 Hypoxia-inducible Factor during Hypoxia Response in Caenorhabditis elegans

Date
2005-05-27
Authors
Nettleton, Dan
Shen, Chuan
Nettleton, Dan
Jiang, Min
Kim, Stuart
Powell-Coffman, Jo Anne
Powell-Coffman, Jo Anne
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StatisticsGenetics, Development and Cell Biology
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 HIF-1α subunit is hydroxylated and is targeted for degradation by the von Hippel-Lindau tumor suppressor protein (VHL). This regulatory pathway is evolutionarily conserved, and the Caenorhabditis elegans hif-1 and vhl-1 genes encode homologs of the HIF-1α 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 mRNA expression. Genes regulated by C. elegans hif-1 have predicted functions in signal transduction, metabolism, transport, and extracellular matrix remodeling. We examined the in vivo requirement for 16 HIF-1 target genes and discovered that the phy-2 prolyl 4-hydroxylase α subunit is critical for survival in hypoxic conditions. Some HIF-1 target genes negatively regulate formation of stress-resistant dauer larvae. The microarray data presented herein also provide clear evidence for an HIF-1-independent pathway for hypoxia response, and this pathway regulates the expression of multiple heat shock proteins and several transcription factors.

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This research was originally published in the Journal of Biological Chemistry. Shen, Chuan, Daniel Nettleton, Min Jiang, Stuart K. Kim, and Jo Anne Powell-Coffman. "Roles of the HIF-1 hypoxia-inducible factor during hypoxia response in Caenorhabditis elegans." Journal of Biological Chemistry 280, no. 21 (2005): 20580-20588. doi: 10.1074/jbc.M501894200. © the American Society for Biochemistry and Molecular Biology.

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