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FASEB Journal

Publication date: 2004-02
Volume: 18 Pages: 358 - 60
ISSN: 0892-6638, 1530-6860 PMID: 14656993
DOI: 10.1096/fj.03-0513fje
Publisher: The Federation of American Societies for Experimental Biology


Catalano, Alfonso
Caprari, Paola ; Rodilossi, Sabrina ; Betta, Piergiacomo ; Castellucci, Mario ; Casazza, Andrea ; Tamagnone, Luca ; Procopio, Antonio


Cell Division, Cell Line, Cell Line, Tumor, Cyclin D1, Enzyme Activation, Epithelial Cells, Feedback, Physiological, Humans, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, Models, Biological, Neoplasms, Semaphorin-3A, Up-Regulation, Vascular Endothelial Growth Factor A, p38 Mitogen-Activated Protein Kinases, 0601 Biochemistry and Cell Biology, 0606 Physiology, 1116 Medical Physiology, Biochemistry & Molecular Biology


Vascular endothelial growth factor (VEGF) and semaphorin-3A (Sema-3A) play important roles in the transduction of promitotic and antimitotic signals, respectively. Here, we report that these conflicting signals are integrated via negative feedback between VEGF and Sema-3A pathways in several primary normal, but not malignant, mesothelial cells. Unlike malignant mesothelial (MM) cells, in which VEGF induces cell proliferation, normal mesothelial (NM) cell growth was repressed by VEGF. Although both cell-types expressed an overlapping set of VEGF tyrosine-kinase receptors, only in NM cells VEGF exposure entails a p38 mitogen-activated protein kinase (MAPK)-dependent increased of Sema-3A production. Inhibition of p38 MAPK (by SB202190 and SB203580) or a dominant-negative mutant of Sema-3A receptor plexin-A1 reversed the inhibitory effects of VEGF in NM cells, increasing cyclin D1 synthesis and cell growth. Conversely, sustained activation of p38 MAPK by the p38 MAPK-activating kinases MKK3 and MKK6 or transfection with Sema-3A inhibited VEGF-induced cyclin D1 up-regulation and MM cell proliferation. Therefore, these results delineate a new role of Sema-3A in VEGF function mediated by p38 MAPK and suggest that the abrogation of regulated Sema-3A expression is responsible for VEGF-driven growth of tumor cells.