Downregulation of delta CaM kinase II in human tumor cells

Over two dozen alternative splice variants of CaMK-II, the type II Ca2+/CaM -dependent protein kinase, are encoded from four genes (alpha, beta, gamma and delta) in mammalian cells. Isozymes of alpha and beta CaMK-II are well characterized in brain; however, an understanding of the relative endogenou s levels of CaMK-II isozymes in a wide variety of non-neuronal cells has no t yet been described. In this study, we have demonstrated that CaMK-II cons ists primarily of the 54 kDa delta CaMK-II (delta(2) or delta(C)) isozyme i n rodent fibroblasts. beta and gamma CaMK-II isozymes are minor and a CaMK- II was not expressed. The primary delta CaMK-II in human fibroblasts and th e MCF10A mammary epithelial cell line was the 52 kDa delta(4) CaMK-II, an i sozyme identical to delta(2) except for a missing 21-amino-acid C-terminal tail. delta CaMK-II levels were diminished in both human and rodent fibrobl asts after SV40 transformation and in the mammary adenocarcinoma MCF7 cell line when compared to MCF10A cells. In fact, most tumor cells exhibited CaM K-II specific activities which were two- to tenfold lower than in untransfo rmed fibroblasts. We conducted complementary CaMK-II studies on the NGF-ind uced differentiation of rat PC-12 cells. Although no new synthesis of CaMK- II occurs, neurite outgrowth in these cells is accompanied by a preferentia l activation of delta CaMK-II. Endogenous delta CaMK-II has a perinuclear d istribution in fibroblasts and extends along neurites in PC-12 cells. These findings point to a role for delta CaMK-II isozymes in cellular differenti ation. (C) 1999 Elsevier Science B.V. All rights reserved.