Linked Life Data

17292911

Source:http://linkedlifedata.com/resource/pubmed/id/17292911

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pubmed-article:17292911pubmed:abstractTextBeta-adrenergic receptor (beta-AR) stimulation induces apoptosis in adult rat ventricular myocytes (ARVM). beta1 integrin signaling plays a protective role in beta-AR-stimulated apoptosis. Glycogen synthase kinase-3beta (GSK-3beta), a multifunctional serine/threonine kinase, negatively regulates cardiac hypertrophy. Here we show that beta-AR stimulation (isoproterenol; 15 min) increases tyr(216) phosphorylation and GSK-3beta activity. Inclusion of LiCl, inhibitor of GSK-3beta, in the reaction mix or expression of catalytically inactive GSK-3beta (KM-GSK) inhibited beta-AR-stimulated GSK-3beta activity. Inhibition of tyrosine kinase using genistein or chelation of intracellular Ca(2+) using BAPTA-AM inhibited beta-AR-stimulated increases in tyr(216) phosphorylation and GSK-3beta activity. Inhibition of GSK-3beta using pharmacological inhibitors or infection with KM-GSK decreased beta-AR-stimulated cytosolic cytochrome C release and apoptosis. Expression of beta1 integrins increased ser(9) phosphorylation and inhibited beta-AR-stimulated increase in GSK-3beta activity. Wortmannin, inhibitor of PI3-kinase, reversed the effects of beta1 integrins on GSK-3beta activity and apoptosis. Purified active matrix metalloproteinase-2 (MMP-2), shown to interfere with beta1 integrin signaling, increased GSK-3beta activity, while inhibition of MMP-2 inhibited beta-AR-stimulated increases in GSK-3beta activity. beta-AR stimulation induced nuclear accumulation of GSK-3beta. beta-AR stimulation (3 h) increased the expression of transcription factor Gadd153 (growth arrest- and DNA damage-inducible gene 153). These data suggest that beta-AR stimulation increases GSK-3beta activity. Activation of GSK-3beta plays a pro-apoptotic role in beta-AR-stimulated apoptosis via the involvement of mitochondrial death pathway. beta1 integrins inactivate GSK-3beta and play an anti-apoptotic role via the involvement of PI3-kinase pathway. The apoptotic effects of GSK-3beta may be mediated, at least in part, via its nuclear localization and induction of pro-apoptotic genes, such as Gadd153.lld:pubmed
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pubmed-article:17292911pubmed:authorpubmed-author:RossRobert...lld:pubmed
pubmed-article:17292911pubmed:authorpubmed-author:SinghKrishnaKlld:pubmed
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pubmed-article:17292911pubmed:authorpubmed-author:MenonBinduBlld:pubmed
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pubmed-article:17292911pubmed:dateRevised2011-11-2lld:pubmed
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pubmed-article:17292911pubmed:articleTitleGlycogen synthase kinase-3beta plays a pro-apoptotic role in beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes: Role of beta1 integrins.lld:pubmed
pubmed-article:17292911pubmed:affiliationDepartment of Physiology, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, PO Box 70576, Johnson City, TN 37614, USA.lld:pubmed
pubmed-article:17292911pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:17292911pubmed:publicationTypeResearch Support, U.S. Gov't, Non-P.H.S.lld:pubmed
pubmed-article:17292911pubmed:publicationTypeResearch Support, N.I.H., Extramurallld:pubmed