Evidence that thrombin-stimulated DNA synthesis in pulmonary arterial fibroblasts involves phosphatidylinositol 3-kinase-dependent p70 ribosomal S6 kinase activation

Belham, C. M., Scott, P. H., Twomey, D. P., Gould, G. W., Wadsworth, R. M. and Plevin, R. (1997) Evidence that thrombin-stimulated DNA synthesis in pulmonary arterial fibroblasts involves phosphatidylinositol 3-kinase-dependent p70 ribosomal S6 kinase activation. Cellular Signalling, 9(1), pp. 109-116. (doi:10.1016/S0898-6568(96)00120-9) (PMID:9067639)

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Abstract

We have examined the regulation of the 70 kDa ribosomal S6 kinase (p70s6k) by the G-protein-coupled receptor agonist α-thrombin and the role of this signalling molecule in the mitogenic effect of thrombin in cultured bovine pulmonary arterial (PA) fibroblasts. Thrombin stimulated p70s6k activity in a time and concentration-dependent manner which was abolished by the macrolide rapamycin. The phosphatidylinositol (PI) 3-kinase inhibitor wortmannin also completely blocked p70s6k activity in response to thrombin but did not affect p70s6k activity evoked by platelet-derived growth factor (PDGF) at a concentration that abrogated PDGF-stimulated PI 3-kinase activity. Activation of p70s6k by thrombin, but not PDGF, was also inhibited (by 48.3 ± 5.4%) by pre-incubation of cells with pertussis toxin (PTX). Downregulation of protein kinase C (PKC) α and ϵ isoforms by pretreatment of fibroblasts for 48 h with phorbol 12-myristate 13-acetate (PMA), markedly attenuated both thrombin and PDGF -stimulated p70s6k activation (by 74.8 ± 4.4% and 82.3 ± 7.9% respectively). Thrombin also strongly stimulated (over 100 fold) the incorporation of [3H]thymidine into growth arrested PA fibroblasts which was inhibited by rapamycin (by 33.6 ± 2.0%). From these results we propose that in PA fibroblasts: 1) thrombin stimulates the activation of p70s6k in a manner consistent with an involvement of a heterotrimeric G protein of the Gi family, a PI 3-kinase other than the PI 3-kinase involved in signalling by PDGF, and PKC. 2) a p70s6k-dependent pathway plays a role in mitogenic signalling by thrombin.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Scott, Dr Pamela
Authors: Belham, C. M., Scott, P. H., Twomey, D. P., Gould, G. W., Wadsworth, R. M., and Plevin, R.
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Cellular Signalling
Publisher:Elsevier
ISSN:0898-6568
ISSN (Online):1873-3913
Published Online:27 August 1997

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