Js. Huang et al., Extracellular calcium stimulates DNA synthesis in synergism with zinc, insulin and insulin-like growth factor I in fibroblasts, EUR J BIOCH, 266(3), 1999, pp. 943-951
In serum-starved mouse NIH 3T3 fibroblasts cultured in 1.8 mM Ca2+-containi
ng medium, addition of 0.75-2 mM extra Ca2+ stimulated DNA synthesis in syn
ergism with zinc (15-60 mu M), insulin and insulin-like growth factor I. Ex
tra Ca2+ stimulated phosphorylation/activation of p42/p44 mitogen-activated
protein kinases by an initially (10 min) zinc-independent mechanism; howev
er, insulin, and particularly zinc, significantly prolonged Ca2+-induced mi
togen-activated protein kinase phosphorylation. Ln addition, extra Ca2+ act
ivated p70 S6 kinase by a zinc-dependent mechanism and enhanced the stimula
tory effect of zinc on choline kinase activity. Insulin and insulin-like gr
owth factor I also commonly increased both p70 S6 kinase and choline kinase
activities. In support of the role of the choline kinase product phosphoch
oline in the mediation of mitogenic Ca2+ effects, cotreatments with the cho
line kinase substrate choline (250 mu M) and the choline kinase inhibitor h
emicholinium-3 (2 mM) enhanced and inhibited, respectively, the combined st
imulatory effect of extra Ca2+ (3.8 mM total) and zinc on DNA synthesis. In
various human skin fibroblast lines, 1-2 mM extra Ca2+ also stimulated DNA
synthesis in synergism with zinc and insulin. The results show that in var
ious fibroblast cultures, high concentrations of extracellular Ca2+ can col
laborate with zinc and certain growth factors to stimulate DNA synthesis. C
onsidering the high concentration of extracellular Ca2+ in the dermal layer
, Ca2+ may promote fibroblast growth during wound healing in concert with z
inc, insulin growth factor-I insulin, and perhaps other growth factors.