Phorbol esters showing selective activation of PKC isozymes in vitro regulate thyroid function and insulin-like...

We have examined the effects of phorbol derivatives which show selective activation of protein kinase C (PKC) isozymes in vitro, on several parameters of thyroid function. Functions examined were iodide uptake and organification, iodocompound secretion and insulin-like growth factor binding protein (IGFBP) secretion, all of which have been shown previously to be modulated by 12-O-tetradecanoylphorbol 13-acetate (TPA), a pan activator of PKC isozymes. All of the agents examined, including DOPPA (12-deoxyphorbol-13-O-phenylacetate-20 acetate), which is specific for the beta 1 isozyme in vitro, were able to mimic the effects of TPA. These effects were evident by 2 h in the iodide uptake and organification assays, by 4 h in the secretion assays and by 8 h in the IGFBP secretion assays. The phorbol derivatives differed from TPA in their ability to down-regulate total PKC activity, DOPPA being weakly effective at 8 h (14.7% inhibition) when TPA had effected > 70% down-regulation of PKC. As the effects of DOPPA were detected by 8 h at the latest, these data indicate that the effects observed were due to PKC activation rather than down-regulation. Furthermore, the differences in down-regulation profiles between DOPPA and TPA suggest that in vivo, DOPPA may maintain its in vitro specificity. We conclude that inhibition of thyroid iodide uptake and its organification, stimulation of iodocompound secretion and stimulation of IGFBP-2 and IGFBP-3 secretion may be effected through the modulation of a limited number of PKC isozymes and possibly initially, only through PKC beta 1.