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J. Biol. Chem., Vol. 277, Issue 47, 45041-45048, November 22, 2002
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From the Chromium(VI) (Cr(VI)) is widely used in industry
and is a potent inducer of tumors in animals. The present study
demonstrates that Cr(VI) induces hypoxia-inducible factor 1 (HIF-1) activity through the specific expression of HIF-1
p38 Signaling-mediated Hypoxia-inducible Factor 1
and Vascular
Endothelial Growth Factor Induction by Cr(VI) in DU145 Human Prostate
Carcinoma Cells*
,§,,,,
Mary Babb Randolph Cancer Center,
Department of Microbiology, Immunology and Cell Biology, West
Virginia University, Morgantown, West Virginia 26506-9300 and
¶ Health Effects Laboratory Division, National Institute for
Occupational Safety and Health, Morgantown, West Virginia 26505
but
not HIF-1
subunit and increases the level of vascular endothelial
growth factor (VEGF) expression in DU145 human prostate carcinoma
cells. To dissect the signaling pathways involved in Cr(VI)-induced
HIF-1 expression, we found that p38 mitogen-activated protein
kinase signaling was required for HIF-1 expression induced by
Cr(VI). Neither phosphatidylinositol 3-kinase nor extracellular
signal-regulated kinase activity was required for Cr(VI)-induced HIF-1
expression. Cr(VI) induced expression of HIF-1 and VEGF through the
production of reactive oxygen species in DU145 cells. The major species
of reactive oxygen species responsible for the induction of HIF-1 and
VEGF expression is H2O2. These results
suggest that the expression of HIF-1 and VEGF induced by Cr(VI) may be
an important signaling pathway in the Cr(VI)-induced carcinogenesis.
*
This work was supported in part by National Institutes of
Health Grants RR16440 and CA60731 and American Heart Association Grant
0160166B.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence may be addressed. Tel.: 304-285-6158;
Fax: 304-285-5938; E-mail: xshi@cdc.gov.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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