Author:
PAGES, GILLES;

MILANINI, JULIE;

RICHARD, DARREN E.;

BERRA, EDURNE;

GOTHIE, EMMANUEL;

VINALS, FRANCESC;

POUYSSEGUR, JACQUES

Insitution:
a Institution Centre de Biochimie,
CNRS-UMR 6543,
Universite de Nice,
Parc
Valrose, 06108
Nice, France

Title:
Signaling Angiogenesis via p42/p44 MAP Kinase Cascade.

[Report] Source:
Annals of the New York Academy of Sciences.
ATHEROSCLEROSIS V THE FIFTH SARATOGA INTERNATIONAL CONFERENCE.
902:187-200,
May 2000.

Abstract

Vascular endothelial growth factor (VEGF), a potent agonist secreted by virtually all cells, controls migration and division of vascular endothelial cells.

"Vascular endothelial growth factor (VEGF)" "is" "a potent agonist"
"VEGF" "is secreted by" "virtually all cells"
"VEGF" "controls migration of" " vascular endothelial cells"
"VEGF" "division of" vascular endothelial cells"

Disruption of one VEGF allele in mice has revealed a dramatic lethal effect in early embryogenesis, suggesting a key role in vasculogenesis.

"Disruption of one VEGF allele in mice" "has revealed" "a dramatic lethal effect"
"the lethal effect" " occurs in" "early embryogenesis"
"the lethal effect" "suggesting" "a key role in vasculogenesis"

We analyzed the regulation of VEGF mRNA in normal and transformed CCL39 fibroblasts and then dissected the VEGF promoter to identify the signaling pathway(s) controlling the activation of this promoter in response to growth factors, oncogenes, and hypoxic stress.

"the regulation of VEGF mRNA" "was analyzed in" "normal CCL39 fibroblasts"
"the regulation of VEGF mRNA" "was analyzed in"transformed CCL39 fibroblasts
"The VEGF promoter" "was" "dissected"
"Dissection" "identified" "the signaling pathway(s) controlling the promoter activation"
" the activated promoter" "responsed to" "growth factors"
" the activated promoter" "responsed to" "oncogenes"
" the activated promoter" "responsed to" "hypoxic stress"

We demonstrated that the p42/p44 MAP kinase signaling cascade controls VEGF expression at least at two levels.

"the p42/p44 MAP kinase signaling cascade" "controls" "VEGF expression"
"the p42/p44 MAP kinase signaling cascade" "controls" at least at two levels"

In normoxic conditions, MAPKs activate the VEGF promoter at the proximal (-88/-66) region where Sp-1/AP-2 factors bind.

" MAPKs" "activate" "in normoxic conditions"
"MAPKs" "activate" "the VEGF promoter"
"MAPKs" "activate at" "the proximal (-88/-66) region"
"Sp-1/AP-2 factors" "bind at" "the proximal (-88/-66) region"

Activation of p42/p44 MAPKs is sufficient to turn on VEGF mRNA

"p42/p44 MAPKs activation" "is sufficient to turn on" "VEGF mRNA"

At low O2 tension, hypoxia inducible factor-1[alpha] (HIF-1[alpha]), a limiting factor rapidly stabilized and phosphorylated, plays a key role in the expression of several genes including VEGF.

At low O2 tension, ?
" hypoxia inducible factor-1[alpha] (HIF-1[alpha])" "is" "a limiting factor"
" hypoxia inducible factor-1[alpha] (HIF-1[alpha])" "is" " rapidly stabilized"
" hypoxia inducible factor-1[alpha] (HIF-1[alpha])" "is" " phosphorylated"
" hypoxia inducible factor-1[alpha] (HIF-1[alpha])" "plays a key role in" "the expression of several genes"
" hypoxia inducible factor-1[alpha] (HIF-1[alpha])" "plays a key role in" "the expression of VEGF"

We demonstrated that p42/p44MAPKs stoichiometrically phosphorylate HIF-1[alpha] in vitro and that HIF-1-dependent VEGF gene expression is strongly enhanced by the exclusive activation of p42/p44MAPKs.

" p42/p44MAPKs" "stoichiometrically phosphorylate" "HIF-1[alpha] in vitro"
"HIF-1-dependent VEGF gene expression" "is strongly enhanced by" "the exclusive activation of p42/p44MAPKs"

Finally, we demonstrated that the regulation of p42/p44MAPK activity is critical for controlling proliferation and growth arrest of vascular endothelial cells at confluency.

"regulation of p42/p44MAPK activity" "is critical for" "controlling proliferation at confluency"
"regulation of p42/p44MAPK activity" "is critical for" "growth arrest of vascular endothelial cells at confluency"

These results point to at least three major targets of angiogenesis where p42/p44 MAP kinases exert a determinant action.

" p42/p44 MAP kinases" "exert" "a determinant angiogenesis action"