Roles of the HIF-1 hypoxia-inducible factor during hypoxia response in Caenorhabditis elegans.
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-1alpha 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-1alpha 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 alpha 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.
Shen
Chuan
C
Department of Genetics, Development, and Cell Biology, Iowa State University, Ames 50011, USA.
Nettleton
Daniel
D
Jiang
Min
M
Kim
Stuart K
SK
Powell-Coffman
Jo Anne
JA
D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1; D046228:Microarray Analysis; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010100:Oxygen / Q000008:administration & dosage; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D051793:Hypoxia-Inducible Factor 1; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D011393:Procollagen-Proline Dioxygenase; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010100:Oxygen