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

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

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.


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.