High-intensity p38 kinase activity is critical for p21(cip1) induction andthe antiproliferative function of G(i) protein-coupled receptors

G protein-coupled receptors can stimulate the p38 kinase cascade, but the e ffect this has on cell growth remains poorly characterized. Here we show hu man somatostatin sst(2) and sst(4) receptors inhibit basic fibroblast growt h factor (bFGF)-induced proliferation, via a mechanism that was blocked by the p38 inhibitor PD 169316. The sst(4) receptor could also induce a prolif erative activity in the absence of bFGF, which was unaffected by PD 169316. In contrast, the sst(3) receptor had no effect on basal cell growth or on the proliferation evoked by bFGF. The extracellular signal-regulated kinase activity stimulated by the sst(3) receptor was transient in duration compa red with a sustained activity induced by the sst(2) and sst(4) receptors an d which was critical for the proliferative response of the latter receptor. In addition, activated sst(2) and sst(4) but not sst(3) receptors evoked a prolonged phosphorylation of p38 that was amplified by bFGF. The accumulat ion of the cell cycle inhibitor p21(cip1) was only apparent after sst(2) an d sst(4) receptor activation in the presence of bFGF, which was sensitive t o PD 169316 or pertussis toxin. Thus, the contrasting antiproliferative eff ects evoked by the human sst(2), sst(3), and sst(4) receptors can be accoun ted for by their differential abilities to activate p38. This activity is c ritical for p21(cip1) induction, blockade of entry into S phase, as indicat ed by the lack of retinoblastoma protein phosphorylation, and the associate d antiproliferative activity of somatostatin. Furthermore, by changing the intracellular signaling threshold of p38 through cooperative effects of som atostatin and bFGF, the sst(4) receptor can mediate opposing effects on cel l proliferation.