title: Inhibition of PMA-induced human T cell proliferation by bryostatin is associated with enhanced degradation of conventional protein kinase C (cPKC): Ca2+ signals restore mitogenic activity without abrogating enhanced cPKC degradation.
abstract: Protein kinase C (PKC)-activating tumor promoters, such as PMA, are mitogenic to human T lymphocytes but, in contrast to many physiological mitogenic agonists, PMA does not operate via a receptor-coupled, IL-2-dependent signaling pathway. Bryostatin, another PKC activator, is not mitogenic to human T cells and, moreover, it inhibits the PMA-induced mitogenic response. Inhibition of the PMA-induced human T cell proliferation by bryostatin correlates with the bryostatin-induced increased degradation rate of conventional PKC (cPKC) isoenzymes. Nevertheless, bryostatin synergizes with suboptimal doses of various T cell mitogens operating via a Ca(2+)-dependent signaling pathway to induce a strong IL-2-dependent proliferative response. Our findings indicate that Ca2+ signals do not abolish the bryostatin-induced enhanced degradation rate of cPKC observed in human T cells. The results suggest that transient activation of cPKC by bryostatin induces some irreversible biochemical events that, by themselves, are not sufficient for the induction of cell proliferation, but that can be complemented by a Ca(2+)-mediated signal(s) leading to IL-2-dependent T cell proliferation. In contrast, PMA-induced IL-2-independent proliferation of human T cells appears to be dependent on the continuous presence of cPKC (that may mediate some critical events at late stages of the response) and, therefore, is inhibited by bryostatin, that induces a rapid degradation of potentially active cPKC.
authors.affiliation: Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Galron
authors.forename: A
authors.initials: A
authors.lastname: Tamir
authors.forename: A
authors.initials: A
authors.lastname: Altman
authors.forename: N
authors.initials: N
authors.lastname: Isakov
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D054713:Bryostatins; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D018942:Macrolides; D008934:Mitogens / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D054713:Bryostatins; D007376:Interleukin-2; D007783:Lactones; D018942:Macrolides; D008934:Mitogens; C046785:bryostatin 1; D015759:Ionomycin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium