Bryostatin 1, an activator of protein kinase c, mimics as well as inhibits biological effects of the phorbol ester TPA in vivo and in vitro

The macrocyclic lactone bryostatin 1 activates protein kinase C as effectively as the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Nevertheless, there are only certain TPA-effects that can be induced by bryostatin 1. These include stimulation of epidermal DNA synthesis and alkaline phosphatase activity in vivo as well as activation of the Ca²⁺-independent, phospholipid-requiring phosphorylation of an epidermal protein in a cell-free system. Various other TPA-effects in vivo and in vitro, which are not mimicked by bryostatin 1 can be inhibited by applying bryostatin 130 min prior to TPA. TPA-effects suppressible by bryostatin 1 include the Ca²⁺-dependent stimulation of arachidonic acid and prostaglandin E₂ release, of ornithine decarboxylase (ODC activity and ODC-mRNA expression and of trans-glutaminase activity in keratinocytes in vivo and/or in vitro and, in addition, Epstein-Barr virus induction in Raji cells. The same is true for the conversion step (first stage of promotion) of multistage carcinogenesis. In contrast to the TPA induction of arachidonic acid and prostaglandin E₂ release and of transglutaminase activity, induction by the Ca²⁺-ionophore and by high Ca²⁺-shift, respectively, are not significantly inhibited by bryostatin 1. We suggest that bryostatin 1 might inhibit a specific 'Ca²⁺-component' of TPA action.