One of the advantages of studying
HIF-1 in C. elegans is that mutants lacking hif-1, vhl-1,
or egl-9 are viable in normal culture conditions. Using microarray
studies, we determined that the majority of hypoxia-induced changes in
gene expression required hif-1 function in C. elegans.
We were able to identify genes that were regulated by HIF-1, as well as
genes that were induced by hypoxia independent via HIF-1-independent pathways.
This molecular description of HIF-1 function has provided a foundation
for genetic screens to identify HIF-1 regulators.Shen,
Nettleton, Jiang, Kim, and Powell-Coffman (2005) J Biol Chem. 80:20580
HIF-1 via two pathways. When oxygen levels are high, the
EGL-9 enzyme hydroxylates HIF-1. This covalent modification allows
VHL-1 to target HIF-1 for degradation. Our data show that EGL-9
inhibits HIF-1 via two pathways: In addition to its well-described
role in regulating HIF-1 stability, EGL-9 also functions via a separate,
VHL-1-independent pathway to inhibit HIF-1 activity.
of novel regulators of HIF-1
One of the principal strengths of C. elegans is that it is amenable
to large-scale genetic screens for mutations that disrupt a biological
process of interest. We have designed genetic screens to identify
HIF-1 regulators (rhy genes = regulators of the hypoxia-inducible
factor). RHY-1 is an integral membrane protein that functions in
a negative feedback loop to inhibit HIF-1 function.
Shao, and Powell-Coffman (2006) Genetics 174 p 1205