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GL‐9 regulates the C. elegans hypoxia inducible factor (HIF‐1) by two mechanisms, with differing requirements for EGL‐9 prolyl hydroxylase activity
Author(s) -
Shao Zhiyong,
Zhang Yi,
PowellCoffman Jo Anne
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.lb252
Subject(s) - caenorhabditis elegans , transcription factor , gene , psychological repression , hydroxylation , biology , protein subunit , hypoxia inducible factors , rna interference , microbiology and biotechnology , hypoxia inducible factor 1 , transcription (linguistics) , genetics , biochemistry , gene expression , enzyme , rna , linguistics , philosophy
Animals have to sense and respond to environmental changes in order to survive. For example, when oxygen levels drop below the levels required to sustain normal physiological demands, the hypoxia inducible factor transcription factors (HIFs) implement most of the changes in gene expression that allow animals to survive. HIF heterodimeric complexes include a constitutive beta subunit and an oxygen sensitive alpha subunit. The EGL‐9 / PHD2 dioxygenases catalyze the prolyl hydroxylation of HIFalpha subunits and promote its degradation. This pathway is conserved from Caenorhabditis elegans to humans. We have investigated EGL‐9 function in C. elegans . We found that in addition to regulating HIF‐1 stability, EGL‐9 also suppresses HIF‐1 activity (Shen et al. 2006 Genetics 174:1205). To more fully understand the dual functions of EGL‐9, we have generated and characterized mutations in the endogenous egl‐9 gene and in transgenes. We found that deletion of the conserved MYND domain in EGL‐9 has little effect on either its hydroxylase activity or its ability to suppress HIF‐1 transcriptional activity. Further, we find that inhibition of EGL‐9 catalytic function do not abolish EGL‐9‐mediated repression of HIF‐1 transcriptional activity. We conclude that EGL‐9 regulates HIF‐1‐mediated gene expression by two distinct mechanisms that are separable. This work is funded by NIH GM078424.