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First published online 20 November 2002
doi: 10.1242/jcs.00237
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Research Article |
1 Department of Dermatology, Klinikum der J. W. Goethe-Universität,
Frankfurt am Main, Germany
2 Department of Molecular Biology, Max-Planck-Institut für Physiologische
und Klinische Forschung, Bad Nauheim, Germany
* Author for correspondence (e-mail: Gille{at}em.uni-frankfurt.de)
Accepted 24 October 2002
Hepatocyte growth factor (HGF/SF)-induced expression of vascular
endothelial growth factor (VEGF/VPF) has been implicated in paracrine
amplification of angiogenesis, contributing to angiogenic responses during
inflammation, wound healing, collateral formation and tumor growth. We have
shown previously that HGF/SF-mediated VEGF/VPF expression by keratinocytes is
primarily dependent on transcriptional activation, and we mapped the
HGF/SF-responsive element to a GC-rich region between bp -88 and -65. Sp1-like
factors bind to this element constitutively; however the VEGF/VPF promoter is
transactivated by HGF/SF in the absence of induced binding activity. In
experimental approaches to clarify molecular mechanisms of Sp1-dependent
VEGF/VPF gene transcription, neither HGF/SF-dependent changes in nuclear
expression nor in relative DNA binding activity of Sp family members to the
indicated element were observed. Thus, HGF/SF was hypothesized to induce
VEGF/VPF gene transcription via increased transactivation activity of Sp1
owing to biochemical modification. In immunoprecipitation studies, HGF/SF was
found to increase the amount of serine-phosphorylated Sp1, revealing a likely
mechanism of HGF/SF-induced VEGF/VPF expression, as phosphorylation may
enhance the transcriptional activity of Sp1. The contribution of different
signaling molecules to HGF/SF-induced VEGF/VPF transcription was demonstrated
by the use of chemical inhibition, of expression of kinase-deficient signaling
proteins, and by the use of antisense oligonucleotides. Herein, we provide
evidence that PI 3-kinase, MEK1/2 and PKC-
play a significant role in
HGF/SF-induced VEGF/VPF promoter activation. Together, our results elucidate a
critical pathway of paracrine amplification of angiogenesis, suggesting that
HGF/SF-induced Sp1 phosphorylation may activate VEGF/VPF promoter activity
that requires the contribution of distinct signaling molecules.
Key words: Neovascularization, Endothelial growth factors, HGF/SF, VEGF/VPF, Transcription factors, Trans-activation, Signal transduction, Promoter regions
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