Osmotic stress regulates the stability of cyclin D1 in a p38(SAPK2)-dependent manner

We report here that different cell stresses regulate the stability of cycli n D1 protein. Exposition of Granta 519 cells to osmotic shock, oxidative st ress, and arsenite induced the post-transcriptional down-regulation of cycl in D1. In the case of osmotic shock, this effect was completely reversed by the addition of p38(SAPK2)-specific inhibitors (SB203580 or SB220025), ind icating that this effect is dependent on p38(SAPK2) activity. Moreover, the use of proteasome inhibitors prevented this down-regulation. Thus, osmotic shock induces proteasomal degradation of cyclin D1 protein by a p38(SAPK2) -dependent pathway. The effect of p38(SAPK2) On cyclin D1 stability might b e mediated by direct phosphorylation at specific sites. We found that p38(S APK2) phosphorylates cyclin D1 in vitro at Thr(286) and that this phosphory lation triggers the ubiquitination of cyclin D1. These results link for the first time a stress-induced MAP kinase pathway to cyclin D1 protein stabil ity, and they will help to understand the molecular mechanisms by which str ess transduction pathways regulate the cell cycle machinery and take contro l over cell proliferation.