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.