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 p21waf-1/cip-1 and p27kip-1.

Authors: Zahner, G  Wolf, G  Ayoub, M  Reinking, R  Panzer, U  Shankland, SJ  Stahl, RA 
Citation: Zahner G, etal., J Biol Chem 2002 Mar 22;277(12):9763-71.
Pubmed: (View Article at PubMed) PMID:11756433
DOI: Full-text: DOI:10.1074/jbc.M106307200

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 microg/ml) or NS-398 (3 microm). 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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CRRD Object Information
CRRD ID: 619537
Created: 2002-07-15
Species: All species
Last Modified: 2002-07-16
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.