Differential regulation of the cell cycle by alpha1-adrenergic receptor subtypes

Endocrinology. 2004 Nov;145(11):5157-67. doi: 10.1210/en.2004-0728. Epub 2004 Aug 5.

Abstract

Alpha(1)-Adrenergic receptors have been implicated in growth-promoting pathways. A microarray study of individual alpha(1)-adrenergic receptor subtypes (alpha(1A), alpha(1B), and alpha(1D)) expressed in Rat-1 fibroblasts revealed that epinephrine altered the transcription of several cell cycle regulatory genes in a direction consistent with the alpha(1A)- and alpha(1D)-adrenergic receptors mediating G(1)-S cell cycle arrest and the alpha(1B-)mediating cell-cycle progression. A time course indicated that in alpha(1A) cells, epinephrine stimulated a G(1)-S arrest, which began after 8 h of stimulation and maximized at 16 h, at which point was completely blocked with cycloheximide. The alpha(1B)-adrenergic receptor profile also showed unchecked cell cycle progression, even under low serum conditions and induced foci formation. The G(1)-S arrest induced by alpha(1A)- and alpha(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 alpha(1B)-AR fibroblasts, although the microarray did indicate differences in p27(Kip1) RNA levels. Cell counts proved the antimitotic effect of epinephrine in alpha(1A) and alpha(1D) cells and indicated that alpha(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 alpha(1A)- and alpha(1B)-adrenergic receptor effect. The alpha(1B)-subtype native to DDT1-MF2 cells, a smooth muscle cell line, caused progression of the cell cycle. These results indicate that the alpha(1A)- and alpha(1D)-adrenergic receptors mediate G(1)-S cell-cycle arrest, whereas alpha(1B)-adrenergic receptor expression causes a cell cycle progression and may induce transformation in sensitive cell lines.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic Agonists / pharmacology
  • Animals
  • Cell Count
  • Cell Cycle Proteins / metabolism
  • Cell Division / physiology
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / metabolism
  • Epinephrine / pharmacology
  • Fibroblasts / cytology*
  • Fibroblasts / physiology
  • Flow Cytometry
  • G1 Phase / drug effects
  • G1 Phase / physiology*
  • Humans
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / physiology
  • PC12 Cells
  • Rats
  • Receptors, Adrenergic, alpha-1 / genetics
  • Receptors, Adrenergic, alpha-1 / metabolism*
  • S Phase / drug effects
  • S Phase / physiology*
  • Transcription, Genetic / drug effects
  • Tumor Suppressor Proteins / metabolism

Substances

  • Adrenergic Agonists
  • Cdkn1b protein, rat
  • Cell Cycle Proteins
  • Receptors, Adrenergic, alpha-1
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases
  • Epinephrine