Protein kinase C and cancer: what we know and what we do not

Since their discovery in the late 1970s, protein kinase C (PKC) isozymes represent one of the most extensively studied signaling kinases. PKCs signal through multiple pathways and control the expression of genes relevant for cell cycle progression, tumorigenesis and metastatic dissemination. Despite the vast amount of information concerning the mechanisms that control PKC activation and function in cellular models, the relevance of individual PKC isozymes in the progression of human cancer is still a matter of controversy. Although the expression of PKC isozymes is altered in multiple cancer types, the causal relationship between such changes and the initiation and progression of the disease remains poorly defined. Animal models developed in the last years helped to better understand the involvement of individual PKCs in various cancer types and in the context of specific oncogenic alterations. Unraveling the enormous complexity in the mechanisms by which PKC isozymes have an impact on tumorigenesis and metastasis is key for reassessing their potential as pharmacological targets for cancer treatment.Centro de Investigaciones Inmunológicas Básicas y Aplicada

Protein kinase C and cancer: what we know and what we do not

Since their discovery in the late 1970s, protein kinase C (PKC) isozymes represent one of the most extensively studied signaling kinases. PKCs signal through multiple pathways and control the expression of genes relevant for cell cycle progression, tumorigenesis and metastatic dissemination. Despite the vast amount of information concerning the mechanisms that control PKC activation and function in cellular models, the relevance of individual PKC isozymes in the progression of human cancer is still a matter of controversy. Although the expression of PKC isozymes is altered in multiple cancer types, the causal relationship between such changes and the initiation and progression of the disease remains poorly defined. Animal models developed in the last years helped to better understand the involvement of individual PKCs in various cancer types and in the context of specific oncogenic alterations. Unraveling the enormous complexity in the mechanisms by which PKC isozymes have an impact on tumorigenesis and metastasis is key for reassessing their potential as pharmacological targets for cancer treatment.Centro de Investigaciones Inmunológicas Básicas y Aplicada

Phorbol Ester-induced Myeloid Differentiation is Mediated by Protein Kinase C-Alpha and-Delta and not by Protein Kinase C-BetaII, -Epsilon, -Zeta, and -Eta.

It is generally accepted that the multiple, similar protein kinase C (PKC) isoq mes are responsible for different specialized physiol < gical processes, but evidence that directly assigns specific functions to specific isozymes is scarce. To test whether specific PKC isozymes are involved in myeloid differentiation, we have studied the effect of overexpression of PKC-a, -011, -6, -6, -( and -q in 32D, a mouse myeloid progenitor cell line that does not differentiate in response to 12-0-tetradecanoylphorbol-13-acetate (TPA). No significant morphological or phenotypic changes could be observed in unstimulated cells that overexpress any of these isozymes. However, the cell lines that overexpressed PKC-a or -6 had acquired the ability to become mature macrophages 2-6 h after TPA stimulation. The overexpression of PKC-BII, -6, -f, or -q, in contrast, did not permit TPA-induced differentiation. These results indicate that only these two members of the PKC gene family can participate in TPA-induced myeloid differentiatio

CA(2+)-Dependent and Ca(2+)-Independent Isozymes of Protein Kinase C Mediate Exocytosis in Antigen-Stimulated Rat Basophilic RBL-2H3 Cells.

Rat basophilic RBL-2H3 cells, which exhibit Ca(2+)-dependent secretion of granules when stimulated with antigen, contained the Ca(2+)-dependent alpha and beta and the Ca(2+)-independent delta, epsilon, and zeta isoforms of protein kinase C. These isoforms associated, to variable extents (i.e. delta the most and zeta the least), with the membrane fraction upon antigen stimulation but without external Ca2+; only the Ca(2+)-independent isoforms did so. Both types of isozymes were probably necessary for optimal responses to antigen as indicated by the following observations. All Ca(2+)-dependent isozymes were degraded in cells treated with 20 nM phorbol 12-myristate 13-acetate for 6 h, whereas the Ca(2+)-independent isozymes were not degraded and were retained when the cells were subsequently permeabilized and washed. Cells so treated still exhibited antigen-induced secretion (25-33% of normal) which was suppressed by selective inhibitors of protein kinase C (Ro31-7549 and calphostin C) thereby indicating a possible contribution of the Ca(2+)-independent isozymes in secretion. Normally, washed permeabilized cells lost all isozymes of protein kinase C and failed to secrete in response to antigen. A full secretory response to antigen could be reconstituted by the subsequent addition of nanomolar concentrations of either beta or delta isozymes of protein kinase C (other isozymes were much less effective) but only in the presence of 1 microM free Ca2+ to indicate distinct roles for Ca2+ and protein kinase C in exocytosis

Apoptosis and lipoapoptosis in the fission yeast Schizosaccharomyces pombe

10.1016/j.femsyr.2005.07.004FEMS Yeast Research5121199-1206FYRE