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Differential Regulation of the Cell Cycle by ₁-Adrenergic Receptor Subtypes

Department of Physiology and Pharmacology (J.Y.), Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272; and Department of Molecular Cardiology (P.J.G.-C., T.S., D.F.M., B.R.R., D.M.P.), The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195

Address all correspondence and requests for reprints to: Dianne M. Perez, The Department of Molecular Cardiology NB50, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195. E-mail: perezd{at}ccf.org.

₁-Adrenergic receptors have been implicated in growth-promoting pathways. A microarray study of individual ₁-adrenergic receptor subtypes (_1A, _1B, and _1D) expressed in Rat-1 fibroblasts revealed that epinephrine altered the transcription of several cell cycle regulatory genes in a direction consistent with the _1A- and _1D-adrenergic receptors mediating G₁-S cell cycle arrest and the _1B-mediating cell-cycle progression. A time course indicated that in _1A cells, epinephrine stimulated a G₁-S arrest, which began after 8 h of stimulation and maximized at 16 h, at which point was completely blocked with cycloheximide. The _1B-adrenergic receptor profile also showed unchecked cell cycle progression, even under low serum conditions and induced foci formation. The G₁-S arrest induced by _1A- and _1D-adrenergic receptors was associated with decreased cyclin-dependent kinase-6 and cyclin E-associated kinase activities and increased expression of the cyclin-dependent kinase inhibitor p27^Kip1, all of which were blocked by prazosin. There were no differences in kinase activities and/or expression of p27^Kip1 in epinephrine _1B-AR fibroblasts, although the microarray did indicate differences in p27^Kip1 RNA levels. Cell counts proved the antimitotic effect of epinephrine in _1A and _1D cells and indicated that _1B-adrenergic receptor subtype expression was sufficient to cause proliferation of Rat-1 fibroblasts independent of agonist stimulation. Analysis in transfected PC12 cells also confirmed the _1A- and _1B-adrenergic receptor effect. The _1B-subtype native to DDT1-MF2 cells, a smooth muscle cell line, caused progression of the cell cycle. These results indicate that the _1A- and _1D-adrenergic receptors mediate G₁-S cell-cycle arrest, whereas _1B-adrenergic receptor expression causes a cell cycle progression and may induce transformation in sensitive cell lines.

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