期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 280, 期 21, 页码 20580-20588出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M501894200
关键词
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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 alpha 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 alpha 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.
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