cAMP inhibits linoleic acid-induced growth by antagonizing p27(kip1) depletion, but not interfering with the extracellular signal-regulated kinase or AP-1 activities.
To understand the underlying signaling events of polyunsaturated fatty acid-induced growth, we studied the effect of cAMP on early and delayed growth response events induced by linoleic acid in smooth muscle cells (SMC). cAMP significantly inhibited both basal and linoleic acid-induced DNA synthesis. Linoleic acid-induced early growth response events, such as activation of ERKs, induction of expression of c-fos and jun-B and stimulation of AP-1 activity, however, were not affected by cAMP. In contrast, linoleic acid-induced c-jun expression was blocked by cAMP. cAMP alone stimulated ERKs activation, c-fos and jun-B expression and increased AP-1 activity. Linoleic acid induced depletion of p27kip1 and increased CDK2 activity, events required for G1/S transition. In contrast to early growth response events, linoleic acid-induced G1/S transition signals were significantly inhibited by cAMP. These findings suggest that in addition to inducing immediate early growth response events, linoleic acid mimics growth factors in activating cell cycle events that are associated with G1/S transition in SMC and the negative regulation of linoleic acid-induced growth by cAMP is apparently due to its antagonism with linoleic acid-induced p27kip1 depletion and CDK2 activation.
Division of Cardiology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Z Y
ZY
Hu
N R
NR
Madamanchi
G N
GN
Rao
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D019787:Linoleic Acid / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005576:Colforsin; D004247:DNA; D019787:Linoleic Acid; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases