Protein kinase C (PKC) is the receptor for tumor promoting phorbol esters, which are potent activators of conventional and novel PKCs, but persistent treatment with phorbol esters leads to downregulation of these PKCs. However, PKC eta, a novel PKC isozyme, resists downregulation by tumor-promoting phorbol esters, but little is known about how PKC eta level is regulated. Phosphorylation and dephosphorylation play an important role in regulating activity and stability of PKCs. In the present study, we have investigated the molecular mechanism of PKC eta regulation. Several PKC activators, including phorbol 12,13-dibutyrate, 12-O-tetradecanoylphorbol-13-acetate and indolactam V caused upregulation of PKC eta, whereas the general PKC inhibitor GO 6983, but not the conventional PKC inhibitor Go 6976 led to the downregulation of PKC-eta. Upregulation of PKC eta was associated with an increase in phosphorylation of PKC eta. Silencing of phosphoinositide-dependent kinase-1, which phosphorylates PKC eta at the activation loop, failed to prevent PKC activator-induced upregulation of PKC eta. Knockdown of PKC epsilon but not PKC alpha inhibited PKC activator-induced upregulation of PKC-eta. Thus, our results suggest that the regulation of PKC eta is unique and PKC epsilon is required for the PKC activator-induced upregulation of PKC-eta. (C) 2012 Elsevier Inc. All rights reserved.