High-Intensity p38 Kinase Activity Is Critical for p21^cip1 Induction and the Antiproliferative Function of G_i Protein-Coupled Receptors

Abstract

G protein-coupled receptors can stimulate the p38 kinase cascade, but the effect this has on cell growth remains poorly characterized. Here we show human somatostatin sst₂ and sst₄receptors inhibit basic fibroblast growth factor (bFGF)-induced proliferation, via a mechanism that was blocked by the p38 inhibitor PD 169316. The sst₄ receptor could also induce a proliferative activity in the absence of bFGF, which was unaffected by PD 169316. In contrast, the sst₃ receptor had no effect on basal cell growth or on the proliferation evoked by bFGF. The extracellular signal-regulated kinase activity stimulated by the sst₃receptor was transient in duration compared with a sustained activity induced by the sst₂ and sst₄ receptors and which was critical for the proliferative response of the latter receptor. In addition, activated sst₂ and sst₄but not sst₃ receptors evoked a prolonged phosphorylation of p38 that was amplified by bFGF. The accumulation of the cell cycle inhibitor p21^cip1 was only apparent after sst₂ and sst₄ receptor activation in the presence of bFGF, which was sensitive to PD 169316 or pertussis toxin. Thus, the contrasting antiproliferative effects evoked by the human sst₂, sst₃, and sst₄ receptors can be accounted for by their differential abilities to activate p38. This activity is critical for p21^cip1 induction, blockade of entry into S phase, as indicated by the lack of retinoblastoma protein phosphorylation, and the associated antiproliferative activity of somatostatin. Furthermore, by changing the intracellular signaling threshold of p38 through cooperative effects of somatostatin and bFGF, the sst₄ receptor can mediate opposing effects on cell proliferation.