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J. Biol. Chem., Vol. 277, Issue 12, 9763-9771, March 22, 2002

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Cyclooxygenase-2 Overexpression Inhibits Platelet-derived Growth Factor-induced Mesangial Cell Proliferation through Induction of the Tumor Suppressor Gene p53 and the Cyclin-dependent Kinase Inhibitors p21^waf-1/cip-1 and p27^kip-1*

Gunther Zahner^§, Gunter Wolf, Murwan Ayoub, Rüdiger Reinking, Ulf Panzer, Stuart J. Shankland^¶, and Rolf A. K. Stahl

From the  Department of Medicine, Division of Nephrology and Osteology, University of Hamburg, 20246 Hamburg, Germany and the ^¶ Department of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle, Washington 98104

Cyclooxygenase-2 (COX-2) is an inducible enzyme and serves as a source of paracrine prostaglandin E2 (PGE2) formation in many tissues. In glomerular immune injury COX-2 formation is up-regulated in association with increased mesangial cell growth. To examine whether COX-2 exerts growth modulating effects on glomerular cells, we established two separate COX-2-overexpressing mesangial cell lines (COX-2+) and assessed their proliferative response to the potent mesangial cell growth-promoting factor, platelet-derived growth factor (PDGF). PDGF increased proliferation in mock-transfected cells. In contrast, PDGF did not induce proliferation in COX-2+ cells. Our results also showed that the tumor suppressor protein p53 and the cyclin-dependent kinase inhibitors p21^cip-1 and p27^kip-1 were up-regulated in COX-2+ cells de novo as well as under PDGF-stimulated conditions. To study whether COX-2 products are required for these effects, COX-2+ cells were treated with indomethacin (1 µg/ml) or NS-398 (3 µM). Unexpectedly, both COX inhibitors had no significant effect on cell proliferation, not on the protein levels of p53, p21^cip-1, or p27^kip-1. To evaluate the role of p21^cip-1 and p27^kip-1, COX-2 was overexpressed in mesangial cells derived from p21^cip-1 (p21/ COX-2+) and p27^kip-1 (p27/ COX-2+) null mice. In contrast to the wild type COX-2+ cells, p21/ COX-2+ and p27/ COX-2+ cells proliferated in response to PDGF. These data suggest that COX-2 inhibits mesangial cell proliferation by a novel mechanism that is independent of prostaglandin synthesis, but involves p53, p21^cip-1, and p27^kip-1.

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