Fibroblast growth factor-2 transiently activates the p53 oncosuppressor protein in human primary vascular smooth muscle cells: implications for atherogenesis.
OBJECTIVE
The development of atherosclerotic lesions associates with the proliferation of vascular smooth muscle cells (VSMC), and their migration from arterial tunica media to the intima. Fibroblast growth factor (FGF)-2 can trigger either phenomena, which are accompanied by the functional impairment of the p53 transcription factor. However, FGF-2 impact on p53 function in VSMC is largely unknown.


RESULTS
RT-PCR and Western blot analyses assayed FGF-2 effect on human primary VSMC expression of p53-induced molecules with a role in atherogenesis. Confocal microscopy evaluated whether FGF-2 could affect p53 distribution inside VSMC. Results indicate that VSMC exposure to FGF-2 at amounts stimulating the proliferation and migration of these cells promotes p53 phosphorylation and transient accumulation in VSMC nuclei. This is followed by an increase in the expression of the p53-induced thrombospondin (TSP)-1, a VSMC growth and motility factor, and human double minute 2 (HDM2), an antagonist of p53 transcriptional and growth suppressive activity. At later time points, in agreement with the increase of HDM2 and with the capability of this protein to export nuclear p53 to the cytoplasm, the content of p53 in VSMC nuclei is reduced, and the expression of the p53-targeted TSP-l and HDM2 is diminished.


CONCLUSIONS
Since FGF-2, p53, TSP-1, and HDM2 are expressed in human atherosclerotic lesions, the in vitro effects of FGF-2 described herein may be operative in vivo, providing a molecular mechanism for FGF-2 pro-atherogenic activity.
Barillari
Giovanni
G
Department of Experimental Medicine, University Tor Vergata, Rome, Italy. barillar@uniroma2.it
Iovane
André
A
Bonuglia
Margherita
M
Albonici
Loredana
L
Garofano
Paolo
P
Di Campli
Emanuela
E
Falchi
Mario
M
Condò
Ivano
I
Manzari
Vittorio
V
Ensoli
Barbara
B
D050197:Atherosclerosis; D015153:Blotting, Western; D002465:Cell Movement; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019700:Thrombospondin 1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C495901:TP53 protein, human; D019700:Thrombospondin 1; D016159:Tumor Suppressor Protein p53; D016222:Fibroblast Growth Factor 2; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2