Hypoxia-inducible factor 1 levels vary exponentially over a
physiologically relevant range of o2 tension.
Jiang, Bing-Hua, Gregg L. Semenza, Christian Bauer, and Hugo H. Marti.
Center for Medical Genetics, Departments of Pediatrics and
Medicine, The Johns Hopkins University School of Medicine, Baltimore,
Maryland; and Institute of Physiology, University of Zurich-Irchel,
Zurich, Switzerland
APStracts 3:0134C, 1996.
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix
-loop-helix protein implicated in the transcriptional activation of
genes encoding erythropoietin, glycolytic enzymes, and vascular
endothelial growth factor in hypoxic mammalian cells. In this study,
we have quantitated HIF-1 DNA-binding activity and protein levels of
the HIF-1[alpha] and HIF-1[beta] subunits in human HeLa cells exposed
to O2 concentrations ranging from 0 to 20% in the absence or presence
of 1 mM KCN to inhibit oxidative phosphorylation and cellular O2
consumption. HIF-1 DNA- binding activity, HIF-1[alpha] protein, and
HIF-1[beta] protein each increased exponentially as cells were
subjected to decreasing O2 concentrations, with a half-maximal
response between 1.5 and 2% O2, and a maximal response at 0.5% O2,
both in the presence and absence of KCN. The HIF-1 response was
greatest over O2 concentrations associated with ischemic/hypoxic
events in vivo. These results provide evidence for the involvement of
HIF-1 in O2 homeostasis and represent a functional characterization
of the putative O2 sensor that initiates hypoxia signal transduction
leading to HIF-1 expression.
Received 18 July 1995; accepted in final form 12 April 1996.
APS Manuscript Number C434-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 8 May 96