beta-adrenergic receptor/cAMP-mediated signaling and apoptosis of S49 lymphoma cells.
beta-Adrenergic receptor (betaAR) activation and/or increases in cAMP regulate growth and proliferation of a variety of cells and, in some cells, promote cell death. In the current studies we addressed the mechanism of this growth reduction by examining betaAR-mediated effects in the murine T-lymphoma cell line S49. Wild-type S49 cells, derived from immature thymocytes (CD4(+)/CD8(+)) undergo growth arrest and subsequent death when treated with agents that increase cAMP levels (e.g., betaAR agonists, 8-bromo-cAMP, cholera toxin, forskolin). Morphological and biochemical criteria indicate that this cell death is a result of apoptosis. In cyc(-) and kin(-) S49 cells, which lack G(s)alpha and functional protein kinase A (PKA), respectively, betaAR activation of G(s)alpha and cAMP action via PKA are critical steps in this apoptotic pathway. S49 cells that overexpress Bcl-2 are resistant to cAMP-induced apoptosis. We conclude that betaAR activation induces apoptosis in immature T lymphocytes via G(s)alpha and PKA, while overexpression of Bcl-2 prevents cell death. betaAR/cAMP/PKA-mediated apoptosis may provide a means to control proliferation of immature T cells in vivo.
Yan
L
L
Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0636, USA.
Herrmann
V
V
Hofer
J K
JK
Insel
P A
PA
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D016193:G1 Phase / Q000187:drug effects; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008223:Lymphoma / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D019253:Proto-Oncogene Proteins c-bcl-2; D011943:Receptors, Adrenergic, beta; D011994:Recombinant Proteins; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D007545:Isoproterenol