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Synergistic Antiproliferative Actions of Cyclic Adenosine 3',5'-Monophosphate, Interleukin-1ß, and Activators of Ca²⁺/Calmodulin-Dependent Protein Kinase in Primary Hepatocytes¹

Departments of Anatomy and Cell Biology (G.M., T.B., O.K.V., S.O.D.) and Biochemistry and Molecular Biology (A.P.D., T.F.), University of Bergen, N-5009 Bergen, Norway

Address all correspondence and requests for reprints to: Dr. Stein Ove Døskeland, Department of Anatomy and Cell Biology, University of Bergen, Årstadveien 19, N-5009 Bergen, Norway. E-mail: stein.doskeland{at}med.uib.no

cAMP and Ca²⁺ acted together with the acute phase cytokine interleukin-1ß (IL-1ß) to inhibit hepatocyte DNA replication. At sub-basal activity of cAMP-dependent protein kinase (PKA), neither IL-1ß nor the Ca²⁺-elevating hormone vasopressin affected hepatocyte proliferation. Basal level of PKA activity permitted IL-1ß action. Increased PKA activity also permitted vasopressin action and sensitized further towards IL-1ß, which acted at 10–50 pM concentrations. Vasopressin acted via Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), and its action was mimicked by the serine/threonine phosphatase inhibitor microcystin, which activates CaMKII. Inhibitors (KN93 and KT5926) of CaMKII selectively counteracted the effects of vasopressin and microcystin on hepatocyte proliferation at concentrations similar to those required to inhibit CaMKII in vitro. Two-dimensional gel electrophoresis of ³²P-prelabeled hepatocytes revealed a common set of proteins phosphorylated in response to vasopressin and microcystin. Their phosphorylation was counteracted by CaMKII inhibitor (KT5926). Phosphorylation of the CaMKII substrate phenylalanine hydroxylase (PAH; EC 1.14.16.1) was used as an endogenous marker of CaMKII activation. It was found that treatment of the cells with vasopressin or microcystin increased the phosphorylation of PAH, and that the vasopressin-induced PAH phosphorylation was inhibited by KT5926. In conclusion, the Ca²⁺-elevating hormone vasopressin potentiated the antiproliferative effects of cAMP and IL-1ß through CaMKII activation.

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