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Research ArticleArticle

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

Forbes Alderton, Patrick P. A. Humphrey and Lynda A. Sellers
Molecular Pharmacology May 2001, 59 (5) 1119-1128; DOI: https://doi.org/10.1124/mol.59.5.1119
Forbes Alderton
Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
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Patrick P. A. Humphrey
Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
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Lynda A. Sellers
Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
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This article has a correction. Please see:

  • Correction to “High-intensity p38 kinase activity is critical for p21 cip1 induction and the antiproliferative function of Gi protein-coupled receptors” - July 01, 2001

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 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.

Footnotes

    • Received January 22, 2001.
    • Accepted September 7, 2000.
  • Send reprint requests to: Dr. L. A. Sellers, Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Tennis Court Rd., Cambridge, CB2 1QJ, UK. E-mail: wtem15797{at}glaxowellcome.co.uk

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Molecular Pharmacology: 59 (5)
Molecular Pharmacology
Vol. 59, Issue 5
1 May 2001
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Research ArticleArticle

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

Forbes Alderton, Patrick P. A. Humphrey and Lynda A. Sellers
Molecular Pharmacology May 1, 2001, 59 (5) 1119-1128; DOI: https://doi.org/10.1124/mol.59.5.1119

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Research ArticleArticle

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

Forbes Alderton, Patrick P. A. Humphrey and Lynda A. Sellers
Molecular Pharmacology May 1, 2001, 59 (5) 1119-1128; DOI: https://doi.org/10.1124/mol.59.5.1119
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