High-intensity p38 kinase activity is critical for p21(cip1) induction and the antiproliferative function of G(i) protein-coupled receptors.
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 sst(2) and sst(4) receptors inhibit basic fibroblast growth factor (bFGF)-induced proliferation, via a mechanism that was blocked by the p38 inhibitor PD 169316. The sst(4) receptor could also induce a proliferative 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 compared with a sustained activity induced by the sst(2) and sst(4) receptors and 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 accumulation of the cell cycle inhibitor p21(cip1) was only apparent after sst(2) and sst(4) 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 sst(2), sst(3), and sst(4) 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 sst(4) receptor can mediate opposing effects on cell proliferation.
Alderton
F
F
Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.
Humphrey
P P
PP
Sellers
L A
LA
D051698:Activating Transcription Factor 2; D000818:Animals; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004347:Drug Interactions; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006801:Humans; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D037342:Pertussis Toxin; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D017481:Receptors, Somatostatin / Q000096:biosynthesis / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism; D050796:STAT3 Transcription Factor; D013004:Somatostatin / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; C493956:CDKN1A protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D017481:Receptors, Somatostatin; D016160:Retinoblastoma Protein; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D010566:Virulence Factors, Bordetella; C106140:somatostatin receptor sst2A; C101130:somatostatin receptor type 1; D016222:Fibroblast Growth Factor 2; D014443:Tyrosine; D013004:Somatostatin; D037342:Pertussis Toxin; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go