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Vol. 56, Issue 5, 1079-1086, November 1999

beta 2-Adrenergic Receptor Agonists and cAMP Arrest Human Cultured Airway Smooth Muscle Cells in the G1 Phase of the Cell Cycle: Role of Proteasome Degradation of Cyclin D1

Alastair G. Stewart, Trudi Harris, Darren J. Fernandes, Leslie C. Schachte, Valentina Koutsoubos, Elizabeth Guida, Claire E. Ravenhall, Peter Vadiveloo, and John W. Wilson

Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia (A.G.S., T.H., D.J.F., V.K., E.G., C.E.R.); Bernard O'Brien Institute of Microsurgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia (L.C.S., P.V.); and Respiratory Medicine, Alfred Hospital, Prahran, Victoria, Australia (J.W.W.).

Hyperplasia of airway smooth muscle (ASM) contributes to the airway hyperresponsiveness that characterizes asthma. We have investigated the relationship between cAMP-induced growth arrest of ASM cells and thrombin-stimulated, extracellular-regulated protein kinase (ERK) activity, cyclin D1, and the restriction protein retinoblastoma. The beta 2-adrenergic receptor agonist albuterol (100 nM) inhibited DNA synthesis after incubation with ASM for periods as brief as 1 h when these coincided with the timing of the restriction point. Inhibition of thrombin-stimulated DNA synthesis by albuterol (1-100 nM), 8-bromo-cAMP (300 µM), or prostaglandin E2 (1 µM) was accompanied by a reduction in cyclin D1 protein levels. The ERK kinase inhibitor PD98059 (3-30 µM) attenuated thrombin-stimulated ERK phosphorylation and activity and the increase in cyclin D1 protein levels, as did albuterol (1-100 nM) or 8-bromo-cAMP (300 µM). In contrast, neither albuterol (100 nM) nor PD98059 (30 µM) reduced cyclin D1 mRNA levels between 4 and 20 h after thrombin addition, which suggests that elevation of cAMP regulates cyclin D1 by a post transcriptional mechanism. The proteasome inhibitor MG132 (30 and 100 nM) and the calpain I inhibitor N-acetyl-Leu-Leu-leucinal (10 µM) attenuated the reduction in thrombin-stimulated cyclin D1 levels in ASM exposed to albuterol (100 nM), 8-bromo-cAMP (300 µM), or the phosphodiesterase inhibitor isobutylmethylxanthine (100 µM). Thus, the cAMP-induced arrest of ASM in the G1 phase of the cell cycle is associated with a proteasomal degradation of cyclin D1 protein and a reduced protein retinoblastoma phosphorylation that prevents passage through the restriction point.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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