Growth inhibition by protein kinase C late in mitogenesis

Abstract

The importance of α-thrombin in the clotting cascade is well-known, but it is also a potent mitogen^1–3. Like many other mitogens, thrombin causes receptor-mediated activation of a phosphatidy-linositol-specific phospholipase C (PLC), leading to the release of diacylglycerol and the subsequent activation of protein kinase C (refs 3–6). Protein kinase C is probably important in cell proliferation, as activation of this enzyme by phorbol esters promotes growth in many systems^4–6. Some growth factors have tyrosine kinase activity and function without activation of PLC or protein kinase C^7–9 . In this report we show that α-thrombin retains its mitogenicity in vascular smooth muscle cells depleted of protein kinase C. Phorbol-12-myristate-13-acetate (PMA) is found to be a potent growth inhibitor when added to vascular smooth muscle cells with α-thrombin. Moreover, growth inhibition is maximal when protein kinase C is activated 4 hours after exposure to thrombin, long after the completion of 'early events' induced by thrombin. Thus, PMA probes an event late in the G₁ phase of the cell cyle or at the G₁–S transition.