Dual action of hydroxylated diphenylethylene estrogens on protein kinase C1.

Protein kinase C (PKC) I (gamma), II (beta) and III (alpha) subspecies are all activated by 1,1-di-(p-hydroxyphenyl)ethylene derivatives (DPE) at micromolar concentrations. This PKC activation depends on the presence of both Ca2+ and phosphatidylserine (PS) but does not require diacylglycerol (DG). DPEs enhance PKC activity at low PS concentrations, but not at saturating PS concentrations. Like DG, DPEs increase the apparent affinity of PKC for PS as well as for Ca2+, but lead to a decrease in the catalytic activity (Vmax). In the presence of saturating DG concentrations, DPEs exhibit an inhibitory action. The derivatives also inhibit the activity of the proteolytic fragment of PKC, protein kinase M. It is concluded that DPEs are mixed-type inhibitors, probably interacting with the catalytic domain of the enzyme.