RT Journal Article
SR Electronic
T1 High-Intensity p38 Kinase Activity Is Critical for p21<sup>
<em>cip1</em>
</sup> Induction and the Antiproliferative Function of G<sub>i</sub> Protein-Coupled Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1119
OP 1128
DO 10.1124/mol.59.5.1119
VO 59
IS 5
A1 Forbes Alderton
A1 Patrick P. A. Humphrey
A1 Lynda A. Sellers
YR 2001
UL http://molpharm.aspetjournals.org/content/59/5/1119.abstract
AB 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 p21cip1 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 p21cip1 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.