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J. Biol. Chem., Vol. 280, Issue 21, 20580-20588, May 27, 2005

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

Chuan Shen, Daniel Nettleton, Min Jiang¶, Stuart K. Kim¶, and Jo Anne Powell-Coffman||

From the Department of Genetics, Development, and Cell Biology and the Department of Statistics, Iowa State University, Ames, Iowa 50011 and the ^¶Department of Developmental Biology, Stanford University, Stanford, California 94305

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-1 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-1 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 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.

Received for publication, February 18, 2005

^* This work was supported by grants from the National Institutes of Health and Howard Hughes Medical Institute (to S. K. K.) and an American Heart Association established investigator grant (to J. A. P.-C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Tables S1–S3.

^|| To whom correspondence should be addressed: 2108 Molecular Biology Bldg., Iowa State University, Ames, IA 50011-3260. Tel.: 515-294-3906; E-mail: japc{at}iastate.edu.

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