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Molecular and Cellular Biology, June 2001, p. 3995-4004, Vol. 21, No. 12
Institute of Genetic Medicine, Departments of
Pediatrics and Medicine, The Johns Hopkins University School of
Medicine, Baltimore, Maryland 21287-3914
Received 19 December 2000/Returned for modification 13 March
2001/Accepted 28 March 2001
Hypoxia-inducible factor 1 (HIF-1) is a transcriptional
activator composed of HIF-1
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.12.3995-4004.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
HER2 (neu) Signaling Increases the Rate of
Hypoxia-Inducible Factor 1
(HIF-1
) Synthesis: Novel
Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor
Expression
and HIF-1
subunits. Several dozen
HIF-1 targets are known, including the gene encoding vascular
endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1
expression increases as a result of decreased ubiquitination and
degradation. The tumor suppressors VHL (von Hippel-Lindau
protein) and p53 target HIF-1
for ubiquitination such that
their inactivation in tumor cells increases the half-life of HIF-1
.
Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased
PTEN activity in prostate cancer cells also increases HIF-1
expression by an undefined mechanism. In breast cancer, increased
activity of the HER2 (also known as neu) receptor tyrosine
kinase is associated with increased tumor grade, chemotherapy
resistance, and decreased patient survival. HER2 has also been
implicated as an inducer of VEGF expression. Here we demonstrate that
HER2 signaling induced by overexpression in mouse 3T3 cells or
heregulin stimulation of human MCF-7 breast cancer cells results in
increased HIF-1
protein and VEGF mRNA expression that is
dependent upon activity of PI3K, AKT (also known as protein kinase
B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression,
heregulin stimulation does not affect the half-life of HIF-1
but
instead stimulates HIF-1
synthesis in a rapamycin-dependent manner.
The 5'-untranslated region of HIF-1
mRNA directs
heregulin-inducible expression of a heterologous protein. These data
provide a molecular basis for VEGF induction and tumor angiogenesis by
heregulin-HER2 signaling and establish a novel mechanism for the
regulation of HIF-1
expression.
*
Corresponding author. Mailing address: Institute of
Genetic Medicine, Departments of Pediatrics and Medicine, The Johns
Hopkins University School of Medicine, Baltimore, MD 21287-3914. Phone: (410) 955-1619. Fax: (410) 955-0484. E-mail:
gsemenza{at}jhmi.edu.
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