Protein kinase C, an elusive therapeutic target? (original) (raw)
Castagna, M. et al. Direct activation of calcium-activated, phospholipid-dependent protein-kinase by tumor-promoting phorbo esters. J. Biol. Chem.257, 7847–7851 (1982). This is the first study that suggested a pathological role for PKC in cancer and triggered active research in the scientific community. CASPubMed Google Scholar
Geraldes, P. & King, G. L. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ. Res.106, 1319–1331 (2010). CASPubMedPubMed Central Google Scholar
Toton, E., Ignatowicz, E., Skrzeczkowska, K. & Rybczynska, M. Protein kinase Cɛ as a cancer marker and target for anticancer therapy. Pharmacol. Rep.63, 19–29 (2011). CASPubMed Google Scholar
Inagaki, K., Churchill, E. & Mochly-Rosen, D. Epsilon protein kinase C as a potential therapeutic target for the ischemic heart. Cardiovasc. Res.70, 222–230 (2006). CASPubMed Google Scholar
Ferreira, J. C., Brum, P. C. & Mochly-Rosen, D. βIIPKC and ɛPKC isozymes as potential pharmacological targets in cardiac hypertrophy and heart failure. J. Mol. Cell. Cardiol.51, 479–484 (2011). CASPubMed Google Scholar
Zanin-Zhorov, A., Dustin, M. L. & Blazar, B. R. PKC-θ function at the immunological synapse: prospects for therapeutic targeting. Trends Immunol.32, 358–363 (2011). CASPubMedPubMed Central Google Scholar
Burguillos, M. A. et al. Caspase signalling controls microglia activation and neurotoxicity. Nature472, 319–324 (2011). CASPubMed Google Scholar
Zhang, D., Anantharam, V., Kanthasamy, A. & Kanthasamy, A. G. Neuroprotective effect of protein kinase Cδ inhibitor rottlerin in cell culture and animal models of Parkinson's disease. J. Pharmacol. Exp. Ther.322, 913–922 (2007). CASPubMed Google Scholar
Garrido, J. L., Godoy, J. A., Alvarez, A., Bronfman, M. & Inestrosa, N. C. Protein kinase C inhibits amyloid β peptide neurotoxicity by acting on members of the Wnt pathway. FASEB J.16, 1982–1984 (2002). CASPubMed Google Scholar
Manji, H. K. & Lenox, R. H. The nature of bipolar disorder. J. Clin. Psychiatry61 (Suppl. 13), 42–57 (2000). PubMed Google Scholar
Zarate, C. A. & Manji, H. K. Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder. CNS Drugs23, 569–582 (2009). CASPubMedPubMed Central Google Scholar
Maioli, E. & Valacchi, G. Rottlerin: bases for a possible usage in psoriasis. Curr. Drug Metab.11, 425–430 (2010). CASPubMed Google Scholar
Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science298, 1912–1934 (2002). This is a detailed analysis of kinase inhibitors of the ATP-binding site across the kinome, and it provides effective visual illustrations for the lack of specificity of the inhibitors for specific protein kinases. CASPubMed Google Scholar
Takai, Y., Kishimoto, A., Inoue, M. & Nishizuka, Y. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. 1. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem.252, 7603–7609 (1977). This is the first description of PKC activity by Nishizuka's laboratory. CASPubMed Google Scholar
Takai, Y., Kishimoto, A., Kikkawa, U., Mori, T. & Nishizuka, Y. Unsaturated diacylglycerol as a possible messenger for the activation of calcium-activated, phospholipid dependent protein-kinase system. Biochem. Biophys. Res. Commun.91, 1218–1224 (1979). CASPubMed Google Scholar
Coussens, L. et al. Multiple, distinct forms of bovin and human protein-kinase-C suggest diversity in cellular signaling pathway. Science233, 859–866 (1986). CASPubMed Google Scholar
Ono, Y. et al. The structure, expression, and properties of additional members of the protein kinase C family. J. Biol. Chem.263, 6927–6932 (1988). CASPubMed Google Scholar
Ono, Y. et al. Expression and properties of two types of protein kinase C: alternative splicing from a single gene. Science236, 1116–1120 (1987). CASPubMed Google Scholar
Parker, P. J. et al. The complete primary structure of protein-kinase C — the phorbol ester receptor. Science233, 853–859 (1986). CASPubMed Google Scholar
Hirai, T. & Chida, K. Protein kinase Cζ (PKCζ): activation mechanisms and cellular functions. J. Biochem.133, 1–7 (2003). CASPubMed Google Scholar
Suzuki, A., Akimoto, K. & Ohno, S. Protein kinase Cλ/ι (PKCλ/ι): a PKC isotype essential for the development of multicellular organisms. J. Biochem.133, 9–16 (2003). CASPubMed Google Scholar
Steinberg, S. F. Structural basis of protein kinase C isoform function. Physiol. Rev.88, 1341–1378 (2008). CASPubMed Google Scholar
Persaud, S. D., Hoang, V., Huang, J. & Basu, A. Involvement of proteolytic activation of PKCδ in cisplatin-induced apoptosis in human small cell lung cancer H69 cells. Int. J. Oncol.27, 149–154 (2005). CASPubMed Google Scholar
Newton, A. C. Protein kinase C: structure, function, and regulation. J. Biol. Chem.270, 28495–28498 (1995). This is a review of the family of PKC isozymes. CASPubMed Google Scholar
Konishi, H. et al. Activation of protein kinase C by tyrosine phosphorylation in response to H2O2 . Proc. Natl Acad. Sci. USA94, 11233–11237 (1997). CASPubMedPubMed Central Google Scholar
Konishi, H. et al. Phosphorylation sites of protein kinase Cδ in H2O2-treated cells and its activation by tyrosine kinase in vitro. Proc. Natl Acad. Sci. USA98, 6587–6592 (2001). CASPubMedPubMed Central Google Scholar
Mochly-Rosen, D. Localization of protein kinases by anchoring proteins: a theme in signal transduction. Science268, 247–251 (1995). CASPubMed Google Scholar
Chen, L. et al. Opposing cardioprotective actions and parallel hypertrophic effects of δPKC and ɛPKC. Proc. Natl Acad. Sci. USA98, 11114–11119 (2001). This paper provides the first evidence that the same PKC isozymes may have opposing roles. CASPubMedPubMed Central Google Scholar
Murriel, C. L. & Mochly-Rosen, D. Opposing roles of δ and ɛ PKC in cardiac ischemia and reperfusion: targeting the apoptotic machinery. Arch. Biochem. Biophys.420, 246–254 (2003). CASPubMed Google Scholar
Basu, A. & Pal, D. Two faces of protein kinase Cδ: the contrasting roles of PKCδ in cell survival and cell death. ScientificWorldJournal10, 2272–2284 (2010). CASPubMedPubMed Central Google Scholar
Michie, A. M. & Nakagawa, R. The link between PKCα regulation and cellular transformation. Immunol. Lett.96, 155–162 (2005). CASPubMed Google Scholar
Ishii, H. et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKCβ inhibitor. Science272, 728–731 (1996). CASPubMed Google Scholar
Simonis, G., Braun, M. U., Kirrstetter, M., Schon, S. P. & Strasser, R. H. Mechanisms of myocardial remodeling: ramiprilat blocks the expressional upregulation of protein kinase C-ɛ in the surviving myocardium early after infarction. J. Cardiovasc. Pharmacol.41, 780–787 (2003). CASPubMed Google Scholar
Bowling, N. et al. Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation99, 384–391 (1999). CASPubMed Google Scholar
Palaniyandi, S. S., Sun, L., Ferreira, J. C. & Mochly-Rosen, D. Protein kinase C in heart failure: a therapeutic target? Cardiovasc. Res.82, 229–239 (2009). CASPubMedPubMed Central Google Scholar
Koyanagi, T. et al. Pharmacological inhibition of epsilon PKC suppresses chronic inflammation in murine cardiac transplantation model. J. Mol. Cell. Cardiol.43, 517–522 (2007). CASPubMed Google Scholar
Dempsey, E. C., Cool, C. D. & Littler, C. M. Lung disease and PKCs. Pharmacol. Res.55, 545–559 (2007). CASPubMed Google Scholar
Li, J. & Gobe, G. Protein kinase C activation and its role in kidney disease. Nephrology11, 428–434 (2006). CASPubMed Google Scholar
Tuttle, K. R. Protein kinase C-β inhibition for diabetic kidney disease. Diabetes Res. Clin. Pract.82 (Suppl. 1), 70–74 (2008). Google Scholar
Varin, M. M. et al. In Sjogren's syndrome, B lymphocytes induce epithelial cells of salivary glands into apoptosis through protein kinase Cδ activation. Autoimmun. Rev.11, 252–258 (2012). CASPubMed Google Scholar
Bright, R. & Mochly-Rosen, D. The role of protein kinase C in cerebral ischemic and reperfusion injury. Stroke36, 2781–2790 (2005). CASPubMed Google Scholar
Sun, M.-K. & Alkon, D. L. Pharmacology of protein kinase C activators: cognition-enhancing and antidementic therapeutics. Pharmacol. Therap.127, 66–77 (2010). CAS Google Scholar
Alkon, D. L., Sun, M. K. & Nelson, T. J. PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease. Trends Pharmacol. Sci.28, 51–60 (2007). CASPubMed Google Scholar
Sweitzer, S. M. et al. Protein kinase Cɛ and γ: involvement in formalin-induced nociception in neonatal rats. J. Pharmacol. Exp. Ther.309, 616–625 (2004). CASPubMed Google Scholar
Ytrehus, K., Liu, Y. & Downey, J. M. Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am. J. Physiol.266, H1145–H1152 (1994). CASPubMed Google Scholar
Brooks, G. & Hearse, D. J. Role of protein kinase C in ischemic preconditioning: player or spectator? Circ. Res.79, 627–630 (1996). CASPubMed Google Scholar
Churchill, E. N., Murriel, C. L., Chen, C. H., Mochly-Rosen, D. & Szweda, L. I. Reperfusion-induced translocation of δPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation. Circ. Res.97, 78–85 (2005). CASPubMed Google Scholar
Churchill, E. N., Ferreira, J. C., Brum, P. C., Szweda, L. I. & Mochly-Rosen, D. Ischaemic preconditioning improves proteasomal activity and increases the degradation of δPKC during reperfusion. Cardiovasc. Res.85, 385–394 (2010). CASPubMed Google Scholar
Pratschke, J., Weiss, S., Neuhaus, P. & Pascher, A. Review of nonimmunological causes for deteriorated graft function and graft loss after transplantation. Transpl. Int.21, 512–522 (2008). PubMed Google Scholar
Tanaka, M. et al. Suppression of graft coronary artery disease by a brief treatment with a selective ɛPKC activator and a δPKC inhibitor in murine cardiac allografts. Circulation110 (Suppl. II), 194–199 (2004). Google Scholar
Sarma, N. J., Tiriveedhi, V., Angaswamy, N. & Mohanakumar, T. Role of antibodies to self-antigens in chronic allograft rejection: potential mechanism and therapeutic implications. Hum. Immunol. 9 Jul 2012 [epub ahead of print].
Inagaki, K., Hahn, H. S., Dorn, G. W. & Mochly-Rosen, D. Additive protection of the ischemic heart ex vivo by combined treatment with δ-protein kinase C inhibitor and ɛ-protein kinase C activator. Circulation108, 869–875 (2003). CASPubMed Google Scholar
Lee, M. R., Duan, W. & Tan, S. L. Protein kinase C isozymes as potential therapeutic targets in immune disorders. Expert Opin. Ther. Targets12, 535–552 (2008). CASPubMed Google Scholar
Sledge, G. W. Jr & Gokmen-Polar, Y. Protein kinase C-β as a therapeutic target in breast cancer. Semin. Oncol.33, S15–S18 (2006). CASPubMed Google Scholar
Kim, J., Koyanagi, T. & Mochly-Rosen, D. PKCδ activation mediates angiogenesis via NADPH oxidase activity in PC-3 prostate cancer cells. Prostate71, 946–954 (2011). CASPubMed Google Scholar
Bacher, N., Zisman, Y., Berent, E. & Livneh, E. Isolation and characterization of PKC-L, a new member of the protein kinase C-related gene family specifically expressed in lung, skin, and heart. Mol. Cell. Biol.11, 126–133 (1991). CASPubMedPubMed Central Google Scholar
Krasnitsky, E. et al. PKCη is a novel prognostic marker in non-small cell lung cancer. Anticancer Res.32, 1507–1513 (2012). PubMed Google Scholar
Kim, K. M. et al. PKCθ expression in gastrointestinal stromal tumor. Mod. Pathol.19, 1480–1486 (2006). CASPubMed Google Scholar
Nishikawa, T., Edelstein, D. & Brownlee, M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int. Suppl.77, S26–S30 (2000). CASPubMed Google Scholar
Bezy, O. et al. PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. J. Clin. Invest.121, 2504–2517 (2011). CASPubMedPubMed Central Google Scholar
Manji, H. K. et al. Modulation of CNS signal transduction pathways and gene expression by mood-stabilizing agents: therapeutic implications. J. Clin. Psychiatry60 (Suppl. 2), 27–39; discussion 40–41, 113–116 (1999). PubMed Google Scholar
DiazGranados, N. & Zarate, C. A. Jr. A review of the preclinical and clinical evidence for protein kinase C as a target for drug development for bipolar disorder. Curr. Psychiatry Rep.10, 510–519 (2008). PubMedPubMed Central Google Scholar
Einat, H., Yuan, P., Szabo, S. T., Dogra, S. & Manji, H. K. Protein kinase C inhibition by tamoxifen antagonizes manic-like behavior in rats: implications for the development of novel therapeutics for bipolar disorder. Neuropsychobiology55, 123–131 (2007). CASPubMed Google Scholar
Wang, H. Y., Markowitz, P., Levinson, D., Undie, A. S. & Friedman, E. Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients. J. Psychiatr. Res.33, 171–179 (1999). CASPubMed Google Scholar
Wang, H. Y. & Friedman, E. Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol. Psychiatry40, 568–575 (1996). CASPubMed Google Scholar
Sadeh, J. S. et al. Pustular and erythrodermic psoriasis complicated by acute respiratory distress syndrome. Arch. Dermatol.133, 747–750 (1997). CASPubMed Google Scholar
Nishino, N., Kitamura, N., Hashimoto, T. & Tanaka, C. Transmembrane signalling systems in the brain of patients with Parkinson's disease. Rev. Neurosci.4, 213–222 (1993). CASPubMed Google Scholar
Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nature Biotech.26, 127–132 (2008). CAS Google Scholar
Sobhia, M. E., Grewal, B. K., Bhat, J., Rohit, S. & Punia, V. Protein kinase CβII in diabetic complications: survey of structural, biological and computational studies. Expert Opin. Ther. Targets16, 325–344 (2012). CASPubMed Google Scholar
Wilkinson, S. E., Parker, P. J. & Nixon, J. S. Isoenzyme specificity of bisindolylmaleimides, selective inhibitors of protein kinase C. Biochem. J.294, 335–337 (1993). CASPubMedPubMed Central Google Scholar
Lee, K. W. et al. Enzastaurin, a protein kinase Cβ inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer cells. Cancer Res.68, 1916–1926 (2008). CASPubMed Google Scholar
Gschwendt, M. et al. Rottlerin, a novel protein-kinase inhibitor. Biochem. Biophys. Res. Commun.199, 93–98 (1994). CASPubMed Google Scholar
Soltoff, S. P. Rottlerin: an inappropriate and ineffective inhibitor of PKCδ. Trends Pharmacol. Sci.28, 453–458 (2007). CASPubMed Google Scholar
Zimmermann, J. et al. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and selective inhibitors of protein kinase C (PKC). Arch. Pharm.329, 371–376 (1996). CAS Google Scholar
Cole, D. C. et al. Identification, characterization and initial hit-to-lead optimization of a series of 4-arylamino-3-pyridinecarbonitrile as protein kinase Cθ (PKCθ) inhibitors. J. Med. Chem.51, 5958–5963 (2008). CASPubMed Google Scholar
Pande, V., Ramos, M. J. & Gago, F. The protein kinase inhibitor balanol: structure–activity relationships and structure-based computational studies. Anticancer Agents Med. Chem.8, 638–645 (2008). CASPubMed Google Scholar
Noh, K. M., Hwang, J. Y., Shin, H. C. & Koh, J. Y. A novel neuroprotective mechanism of riluzole: direct inhibition of protein kinase C. Neurobiol. Dis.7, 375–383 (2000). CASPubMed Google Scholar
Blumberg, P. M. In vitro studies on the mode of action of the phorbol esters, potent tumor promoters: part 1. Crit. Rev. Toxicol.8, 153–197 (1980). This is one of the early studies that elucidated the pharmacology of phorbol esters. CASPubMed Google Scholar
Blumberg, P. M. et al. Mechanism of action of the phorbol ester tumor promoters: specific receptors for lipophilic ligands. Biochem. Pharmacol.33, 933–940 (1984). CASPubMed Google Scholar
Marquez, V. E. et al. The transition from a pharmacophore-guided approach to a receptor-guided approach in the design of potent protein kinase C ligands. Pharmacol. Ther.82, 251–261 (1999). CASPubMed Google Scholar
Garcia-Bermejo, M. L. et al. Diacylglycerol (DAG)-lactones, a new class of protein kinase C (PKC) agonists, induce apoptosis in LNCaP prostate cancer cells by selective activation of PKCα. J. Biol. Chem.277, 645–655 (2002). CASPubMed Google Scholar
Workman, P., Kaye, S. B. & Schwartsmann, G. Laboratory and phase I studies of new cancer drugs. Curr. Opin. Oncol.4, 1065–1072 (1992). CASPubMed Google Scholar
Dowlati, A. et al. Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B-cell malignancies. Clin. Cancer Res.9, 5929–5935 (2003). CASPubMed Google Scholar
Szallasi, Z. et al. Bryostatin 1 protects protein kinase C-δ from down-regulation in mouse keratinocytes in parallel with its inhibition of phorbol ester-induced differentiation. Mol. Pharmacol.46, 840–850 (1994). CASPubMed Google Scholar
Wender, P. A., Verma, V. A., Paxton, T. J. & Pillow, T. H. Function-oriented synthesis, step economy, and drug design. Accounts Chem. Res.41, 40–49 (2008). CAS Google Scholar
Shindo, M. et al. Toward the identification of selective modulators of protein kinase C (PKC) isozymes: establishment of a binding assay for PKC isozymes using synthetic C1 peptide receptors and identification of the critical residues involved in the phorbol ester binding. Bioorg. Med. Chem.9, 2073–2081 (2001). CASPubMed Google Scholar
Wender, P. A. et al. Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity. Proc. Natl Acad. Sci. USA108, 6721–6726 (2011). CASPubMedPubMed Central Google Scholar
Wender, P. A. et al. Inspirations from nature. New reactions, therapeutic leads, and drug delivery systems. Pure Appl. Chem.75, 143–155 (2003). CAS Google Scholar
Kraft, A. S., Anderson, W. B., Cooper, H. L. & Sando, J. J. Decrease in cytosolic calcium phospholipid-dependent protein-kinase activity following phorbol ester treatment of EL4 thymoma cells. J. Biol. Chem.257, 3193–3196 (1982). Google Scholar
Disatnik, M. H., Buraggi, G. & Mochly-Rosen, D. Localization of protein kinase C isozymes in cardiac myocytes. Exp. Cell Res.210, 287–297 (1994). CASPubMed Google Scholar
Mochly-Rosen, D., Henrich, C. J., Cheever, L., Khaner, H. & Simpson, P. C. A protein kinase C isozyme is translocated to cytoskeletal elements on activation. Cell Regul.1, 693–706 (1990). CASPubMedPubMed Central Google Scholar
Budas, G. R., Churchill, E. N., Disatnik, M. H., Sun, L. & Mochly-Rosen, D. Mitochondrial import of PKCɛ is mediated by HSP90: a role in cardioprotection from ischaemia and reperfusion injury. Cardiovasc. Res.88, 83–92 (2010). CASPubMedPubMed Central Google Scholar
Goodnight, J. A., Mischak, H., Kolch, W. & Mushinski, J. F. Immunocytochemical localization of eight protein kinase C isozymes overexpressed in NIH 3T3 fibroblasts. Isoform-specific association with microfilaments, Golgi, endoplasmic reticulum, and nuclear and cell membranes. J. Biol. Chem.270, 9991–10001 (1995). CASPubMed Google Scholar
Kim, J. et al. Centrosomal PKCβII and pericentrin are critical for human prostate cancer growth and angiogenesis. Cancer Res.68, 6831–6839 (2008). CASPubMedPubMed Central Google Scholar
Passalacqua, M., Patrone, M., Sparatore, B., Melloni, E. & Pontremoli, S. Protein kinase C-θ is specifically localized on centrosomes and kinetochores in mitotic cells. Biochem. J.337, 113–118 (1999). CASPubMedPubMed Central Google Scholar
Passalacqua, M. et al. Protein kinase C-θ is specifically activated in murine erythroleukaemia cells during mitosis. FEBS Lett.453, 249–253 (1999). CASPubMed Google Scholar
Mochly-Rosen, D., Khaner, H. & Lopez, J. Identification of intracellular receptor proteins for activated protein kinase C. Proc. Natl Acad. Sci. USA88, 3997–4000 (1991). This is the first study to describe RACKs as a means of anchoring activated PKC isozymes to proteins rather than only to lipids. CASPubMedPubMed Central Google Scholar
Hyatt, S. L., Liao, L., Chapline, C. & Jaken, S. Identification and characterization of α-protein kinase C binding proteins in normal and transformed REF52 cells. Biochemistry33, 1223–1228 (1994). CASPubMed Google Scholar
Kheifets, V. & Mochly-Rosen, D. Insight into intra- and inter-molecular interactions of PKC: design of specific modulators of kinase function. Pharmacol. Res.55, 467–476 (2007). CASPubMedPubMed Central Google Scholar
Ron, D. et al. Cloning of an intracellular receptor for protein kinase C: a homolog of the β subunit of G proteins. Proc. Natl Acad. Sci. USA91, 839–843 (1994). CASPubMedPubMed Central Google Scholar
Coussens, L., Rhee, L., Parker, P. J. & Ullrich, A. Alternative splicing increases the diversity of the human protein-kinase C family. DNA6, 389–394 (1987). CASPubMed Google Scholar
Adwan, T. S., Ohm, A. M., Jones, D. N. M., Humphries, M. J. & Reyland, M. E. Regulated binding of importin-α to protein kinase Cδ in response to apoptotic signals facilitates nuclear import. J. Biol. Chem.286, 35716–35724 (2011). CASPubMedPubMed Central Google Scholar
Zinzalla, G. & Thurston, D. E. Targeting protein–protein interactions for therapeutic intervention: a challenge for the future. Future Med. Chem.1, 65–93 (2009). CASPubMed Google Scholar
Souroujon, M. C. & Mochly-Rosen, D. Peptide modulators of protein–protein interactions in intracellular signaling. Nature Biotech.16, 919–924 (1998). This is a review describing how peptide inhibitors of protein–protein interactions can be rationally designed. CAS Google Scholar
Churchill, E. N., Qvit, N. & Mochly-Rosen, D. Rationally designed peptide regulators of protein kinase C. Trends Endocrinol. Metab.20, 25–33 (2009). CASPubMed Google Scholar
Qvit, N. & Mochly-Rosen, D. Highly specific modulators of protein kinase C localization: applications to heart failure. Drug Discov. Today Dis. Mech.7, e87–e93 (2010). CASPubMedPubMed Central Google Scholar
Prekeris, R., Mayhew, M. W., Cooper, J. B. & Terrian, D. M. Identification and localization of an actin-binding motif that is unique to the epsilon isoform of protein kinase C and participates in the regulation of synaptic function. J. Cell Biol.132, 77–90 (1996). CASPubMed Google Scholar
Stebbins, E. G. & Mochly-Rosen, D. Binding specificity for RACK1 resides in the V5 region of βII protein kinase C. J. Biol. Chem.276, 29644–29650 (2001). CASPubMed Google Scholar
Ferreira, J. C. et al. Pharmacological inhibition of βIIPKC is cardioprotective in late-stage hypertrophy. J. Mol. Cell. Cardiol.51, 980–987 (2011). CASPubMedPubMed Central Google Scholar
Caino, M. C., Lopez-Haber, C., Kim, J., Mochly-Rosen, D. & Kazanietz, M. G. Protein kinase Cɛ is required for non-small cell lung carcinoma growth and regulates the expression of apoptotic genes. Oncogene31, 2593–2600 (2012). CASPubMed Google Scholar
Friedman, E., Hoau Yan, W., Levinson, D., Connell, T. A. & Singh, H. Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol. Psychiatry33, 520–525 (1993). CASPubMed Google Scholar
Hahn, C. G. & Friedman, E. Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord.1, 81–86 (1999). CASPubMed Google Scholar
Podar, K., Raab, M. S., Chauhan, D. & Anderson, K. C. The therapeutic role of targeting protein kinase C in solid and hematologic malignancies. Expert Opin. Investig. Drugs16, 1693–1707 (2007). CASPubMed Google Scholar
Ali, A. S., Ali, S., El-Rayes, B. F., Philip, P. A. & Sarkar, F. H. Exploitation of protein kinase C: a useful target for cancer therapy. Cancer Treat. Rev.35, 1–8 (2009). CASPubMed Google Scholar
Reyland, M. E. Protein kinase C isoforms: multi-functional regulators of cell life and death. Front. Biosci.14, 2386–2399 (2009). CASPubMed Central Google Scholar
Bosco, R. et al. Fine tuning of protein kinase C (PKC) isoforms in cancer: shortening the distance from the laboratory to the bedside. Mini Rev. Med. Chem.11, 185–199 (2011). CASPubMed Google Scholar
Teicher, B. A. Protein kinase C as a therapeutic target. Clin. Cancer Res.12, 5336–5345 (2006). CASPubMed Google Scholar
Budas, G. R., Churchill, E. N. & Mochly-Rosen, D. Cardioprotective mechanisms of PKC isozyme-selective activators and inhibitors in the treatment of ischemia-reperfusion injury. Pharmacol. Res.55, 523–536 (2007). CASPubMed Google Scholar
Pravdic, D. et al. Anesthetic-induced preconditioning delays opening of mitochondrial permeability transition pore via protein Kinase C-ɛ-mediated pathway. Anesthesiology111, 267–274 (2009). CASPubMed Google Scholar
Philip, P. A. et al. Phase I study of bryostatin 1: assessment of interleukin 6 and tumor necrosis factor α induction in vivo. J. Natl Cancer Inst.85, 1812–1818 (1993). CASPubMed Google Scholar
Propper, D. J. et al. A phase II study of bryostatin 1 in metastatic malignant melanoma. Br. J. Cancer78, 1337–1341 (1998). CASPubMedPubMed Central Google Scholar
Gonzalez, R., Ebbinghaus, S., Henthorn, T. K., Miller, D. & Kraft, A. S. Treatment of patients with metastatic melanoma with bryostatin-1 — a phase II study. Melanoma Res.9, 599–606 (1999). CASPubMed Google Scholar
Bedikian, A. Y. et al. Phase II evaluation of bryostatin-1 in metastatic melanoma. Melanoma Res.11, 183–188 (2001). CASPubMed Google Scholar
Brockstein, B. et al. Phase II studies of bryostatin-1 in patients with advanced sarcoma and advanced head and neck cancer. Invest. New Drugs19, 249–254 (2001). CASPubMed Google Scholar
Varterasian, M. L. et al. Phase II study of bryostatin 1 in patients with relapsed multiple myeloma. Invest. New Drugs19, 245–247 (2001). CASPubMed Google Scholar
Zonder, J. A. et al. A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer. Clin. Cancer Res.7, 38–42 (2001). CASPubMed Google Scholar
Pfister, D. G. et al. A phase II trial of bryostatin-1 in patients with metastatic or recurrent squamous cell carcinoma of the head and neck. Invest. New Drugs20, 123–127 (2002). CASPubMed Google Scholar
Winegarden, J. D. et al. A phase II study of bryostatin-1 and paclitaxel in patients with advanced non-small cell lung cancer. Lung Cancer39, 191–196 (2003). PubMed Google Scholar
Nezhat, F. et al. Phase II trial of the combination of bryostatin-1 and cisplatin in advanced or recurrent carcinoma of the cervix: a New York Gynecologic Oncology Group study. Gynecol. Oncol.93, 144–148 (2004). CASPubMed Google Scholar
Lam, A. P. et al. Phase II study of paclitaxel plus the protein kinase C inhibitor bryostatin-1 in advanced pancreatic carcinoma. Am. J. Clin. Oncol.33, 121–124 (2010). CASPubMedPubMed Central Google Scholar
Haas, N. B. et al. Weekly bryostatin-1 in metastatic renal cell carcinoma: a phase II study. Clin. Cancer Res.9, 109–114 (2003). CASPubMed Google Scholar
Madhusudan, S. et al. A multicentre phase II trial of bryostatin-1 in patients with advanced renal cancer. Br. J. Cancer89, 1418–1422 (2003). CASPubMedPubMed Central Google Scholar
Ajani, J. A. et al. A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Invest. New Drugs24, 353–357 (2006). This is one of several small studies showing a modest partial response rate with bryostatin 1, but with unacceptable toxicity. The study was discontinued owing to grade 3 or grade 4 myalgias in 50% of patients. CASPubMed Google Scholar
Ku, G. Y. et al. Phase II trial of sequential paclitaxel and 1 h infusion of bryostatin-1 in patients with advanced esophageal cancer. Cancer Chemother. Pharmacol.62, 875–880 (2008). CASPubMed Google Scholar
Cripps, M. C. et al. Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer: a National Cancer Institute of Canada clinical trials group study. Clin. Cancer Res.8, 2188–2192 (2002). CASPubMed Google Scholar
Tolcher, A. W. et al. A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin. Cancer Res.8, 2530–2535 (2002). CASPubMed Google Scholar
Marshall, J. L. et al. A phase II trial of ISIS 3521 in patients with metastatic colorectal cancer. Clin. Colorectal Cancer4, 268–274 (2004). CASPubMed Google Scholar
Advani, R. et al. A phase I trial of aprinocarsen (ISIS 3521/LY900003), an antisense inhibitor of protein kinase C-α administered as a 24-hour weekly infusion schedule in patients with advanced cancer. Invest. New Drugs23, 467–477 (2005). CASPubMed Google Scholar
Rao, S. et al. Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase Cα, in patients with previously treated low-grade non-Hodgkin's lymphoma. Ann. Oncol.15, 1413–1418 (2004). CASPubMed Google Scholar
Lynch, T. J. et al. Randomized phase III trial of chemotherapy and antisense oligonucleotide LY9000003 (ISIS 3521) in patients with advanced NSCLC: initial report. Proc. Am. Soc. Clin. Oncol.22, 623 (2003). Google Scholar
Paz-Ares, L. et al. Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C-α antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer. J. Clin. Oncol.24, 1428–1434 (2006). CASPubMed Google Scholar
Robertson, M. J. et al. Phase II study of enzastaurin, a protein kinase Cβ inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J. Clin. Oncol.25, 1741–1746 (2007). CASPubMed Google Scholar
Morschhauser, F. et al. A phase II study of enzastaurin, a protein kinase Cβ inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Ann. Oncol.19, 247–253 (2008). CASPubMed Google Scholar
Oh, Y. et al. Enzastaurin, an oral serine/threonine kinase inhibitor, as second- or third-line therapy of non-small-cell lung cancer. J. Clin. Oncol.26, 1135–1141 (2008). CASPubMed Google Scholar
Glimelius, B. et al. A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer. Ann. Oncol.21, 1020–1026 (2010). CASPubMed Google Scholar
Kreisl, T. N. et al. A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas. Neuro Oncol.12, 181–189 (2010). CASPubMedPubMed Central Google Scholar
Usha, L. et al. A Gynecologic Oncology Group phase II trial of the protein kinase C-β inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies. Gynecol. Oncol.121, 455–461 (2011). CASPubMedPubMed Central Google Scholar
Socinski, M. A. et al. Randomized, phase II trial of pemetrexed and carboplatin with or without enzastaurin versus docetaxel and carboplatin as first-line treatment of patients with stage IIIB/IV non-small cell lung cancer. J. Thorac. Oncol.5, 1963–1969 (2010). PubMed Google Scholar
Couldwell, W. T. et al. Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Clin. Cancer Res.2, 619–622 (1996). CASPubMed Google Scholar
Bergan, R. C. et al. A Phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer. Clin. Cancer Res.5, 2366–2373 (1999). CASPubMed Google Scholar
Robins, H. I. et al. Phase 2 trial of radiation plus high-dose tamoxifen for glioblastoma multiforme: RTOG protocol BR-0021. Neuro Oncol.8, 47–52 (2006). CASPubMedPubMed Central Google Scholar
Millward, M. J. et al. The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br. J. Cancer95, 829–834 (2006). CASPubMedPubMed Central Google Scholar
Fischer, T. et al. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J. Clin. Oncol.28, 4339–4345 (2010). CASPubMedPubMed Central Google Scholar
Rini, B. I. et al. Time to disease progression to evaluate a novel protein kinase C inhibitor, UCN-01, in renal cell carcinoma. Cancer101, 90–95 (2004). CASPubMed Google Scholar
Welch, S. et al. UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: a study of the Princess Margaret Hospital Phase II consortium. Gynecol. Oncol.106, 305–310 (2007). CASPubMed Google Scholar
Packer, M. et al. Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. J. Am. Coll. Cardiol.22, 65–72 (1993). CASPubMed Google Scholar
DeMets, D. L. & Califf, R. M. Lessons learned from recent cardiovascular clinical trials: part II. Circulation106, 880–886 (2002). PubMed Google Scholar
Aiello, L. P. et al. Oral protein kinase Cβ inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the protein kinase Cβ inhibitor-diabetic retinopathy study and the protein kinase Cβ inhibitor-diabetic retinopathy study 2. Retina31, 2084–2094 (2011). CASPubMed Google Scholar
Ladage, D. et al. Inhibition of PKC α/β with ruboxistaurin antagonizes heart failure in pigs after myocardial infarction injury. Circ. Res.109, 1396–1400 (2011). CASPubMedPubMed Central Google Scholar
Churchill, E. N. & Mochly-Rosen, D. The roles of PKCδ and ɛ isoenzymes in the regulation of myocardial ischaemia/reperfusion injury. Biochem. Soc. Trans.35, 1040–1042 (2007). CASPubMed Google Scholar
Julier, K. et al. Preconditioning by sevoflurane decreases biochemical markers for myocardial and renal dysfunction in coronary artery bypass graft surgery: a double-blinded, placebo-controlled, multicenter study. Anesthesiology98, 1315–1327 (2003). CASPubMed Google Scholar
Guarracino, F. et al. Myocardial damage prevented by volatile anesthetics: a multicenter randomized controlled study. J. Cardiothorac. Vasc. Anesth.20, 477–483 (2006). CASPubMed Google Scholar
Lee, M. C. et al. Isoflurane preconditioning-induced cardio-protection in patients undergoing coronary artery bypass grafting. Eur. J. Anaesthesiol.23, 841–847 (2006). CASPubMed Google Scholar
Tritapepe, L. et al. Cardiac protection by volatile anaesthetics: a multicentre randomized controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Eur. J. Anaesthesiol.24, 323–331 (2007). CASPubMed Google Scholar
De Hert, S. et al. A comparison of volatile and non volatile agents for cardioprotection during on-pump coronary surgery. Anaesthesia64, 953–960 (2009). In this randomized study of 414 patients undergoing CABG, those receiving volatile anaesthetics had reduced 1-year mortality compared to those receiving total intravenous anaesthesia. CASPubMed Google Scholar
Mentzer, R. M. Jr. et al. Adenosine myocardial protection: preliminary results of a phase II clinical trial. Ann. Surg.229, 643–649; discussion 649–650 (1999). PubMedPubMed Central Google Scholar
Belhomme, D. et al. Is adenosine preconditioning truly cardioprotective in coronary artery bypass surgery? Ann. Thorac. Surg.70, 590–594 (2000). CASPubMed Google Scholar
Jin, Z. et al. The myocardial protective effects of adenosine pretreatment in children undergoing cardiac surgery: a randomized controlled clinical trial. Eur. J. Cardiothorac. Surg.39, e90–e96 (2011). PubMed Google Scholar
Mangano, D. T., Miao, Y., Tudor, I. C. & Dietzel, C. Post-reperfusion myocardial infarction: long-term survival improvement using adenosine regulation with acadesine. J. Am. Coll. Cardiol.48, 206–214 (2006). PubMed Google Scholar
Newman, M. F. et al. Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial. JAMA308, 157–164 (2012). This large, randomized study comparing the effect of acadesine versus placebo on the composite end point of mortality, nonfatal stroke and severe left ventricular dysfunction in patients undergoing CABG was stopped prematurely for futility. CASPubMed Google Scholar
Ross, A. M., Gibbons, R. J., Stone, G. W., Kloner, R. A. & Alexander, R. W. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J. Am. Coll. Cardiol.45, 1775–1780 (2005). In this randomized trial of 2,118 patients, adenosine failed to reduce the 6-month incidence of heart failure or death compared to placebo. CASPubMed Google Scholar
Bates, E. et al. Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation117, 886–896 (2008). PubMed Google Scholar
Lincoff, A. M. Selective inhibition of delta protein kinase C to reduce infarct size after primary percutaneous intervention for acute myocardial infarction: the PROTECTION-AMI Phase 2b clinical trial. theheart.org website[online], (2011).
PKC–DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase Cβ Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes54, 2188–2197 (2005).
Aiello, L. P. et al. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology113, 2221–2230 (2006). PubMed Google Scholar
Sheetz, M. J. et al. Effect of ruboxistaurin (RBX) on visual acuity decline over a 6-year period with cessation and reinstitution of therapy: results of an open-label extension of the Protein Kinase C Diabetic Retinopathy Study 2 (PKC-DRS2). Retina31, 1053–1059 (2011). In this long-term study, patients with moderate to severe nonproliferative diabetic retinopathy who received ruboxistaurin for 5 years versus 2 years had a much lower incidence of SMVL (8% versus 26%). CASPubMed Google Scholar
PKC–DMES Study Group. Effect of ruboxistaurin in patients with diabetic macular edema: thirty-month results of the randomized PKC-DMES clinical trial. Arch. Ophthalmol.125, 318–324 (2007).
Campochiaro, P. A. Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest. Ophthalmol. Vis. Sci.45, 922–931 (2004). PubMed Google Scholar
Tuttle, K. R. et al. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care28, 2686–2690 (2005). CASPubMed Google Scholar
Tuttle, K. R., McGill, J. B., Haney, D. J., Lin, T. E. & Anderson, P. W. Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin. J. Am. Soc. Nephrol.2, 631–636 (2007). CASPubMed Google Scholar
Vinik, A. I. et al. Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase Cβ-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial. Clin. Ther.27, 1164–1180 (2005). CASPubMed Google Scholar
Casellini, C. M. et al. A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-β inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy. Diabetes Care30, 896–902 (2007). CASPubMed Google Scholar
Bebchuk, J. M. et al. A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. Arch. Gen. Psychiatry57, 95–97 (2000). CASPubMed Google Scholar
Zarate, C. A. Jr. et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord.9, 561–570 (2007). CASPubMed Google Scholar
Yildiz, A., Guleryuz, S., Ankerst, D. P., Ongur, D. & Renshaw, P. F. Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch. Gen. Psychiatry65, 255–263 (2008). This study showed that inpatients with acute mania who received tamoxifen rather than placebo had significant improvement in their Young Mania Rating Scale. CASPubMed Google Scholar
Amrollahi, Z. et al. Double-blind, randomized, placebo-controlled 6-week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. J. Affect Disord.129, 327–331 (2011). CASPubMed Google Scholar
Budde, K. et al. Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients. Am. J. Transplant.10, 571–581 (2010). CASPubMed Google Scholar
Friman, S. et al. Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients. Am. J. Transplant.11, 1444–1455 (2011). In this study, individuals randomized to an immunosuppressive regimen containing sotrastaurin instead of tacrolimus had a much higher incidence of acute graft rejection. CASPubMed Google Scholar
Begely, C. G. & Ellis, L. M. Raise standards for preclinical cancer reseach. Nature483, 531–533 (2012). This is a good commentary about the challenge of translating preclinical data to successful clinical trials. Google Scholar
Davis, M. I. et al. Comprehensive analysis of kinase inhibitor selectivity. Nature Biotech.29, 1046–1051 (2011). CAS Google Scholar
Saxena, C., Zhen, E., Higgs, R. E. & Hale, J. E. An immuno-chemo-proteomics method for drug target deconvolution. J. Proteome Res.7, 3490–3497 (2008). CASPubMed Google Scholar
Harper, M. T. & Poole, A. W. Diverse functions of protein kinase C isoforms in platelet activation and thrombus formation. J. Thromb. Haemost.8, 454–462 (2010). CASPubMed Google Scholar
Duquesnes, N., Lezoualc'h, F. & Crozatier, B. PKC-delta and PKC-epsilon: foes of the same family or strangers? J. Mol. Cell. Cardiol.51, 665–673 (2011). CASPubMed Google Scholar
Yang, X., Cohen, M. V. & Downey, J. M. Mechanism of cardioprotection by early ischemic preconditioning. Cardiovasc. Drugs Ther.24, 225–234 (2010). PubMedPubMed Central Google Scholar
Chen, C. H. et al. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science321, 1493–1495 (2008). CASPubMedPubMed Central Google Scholar
Ikeno, F., Inagaki, K., Rezaee, M. & Mochly-Rosen, D. Impaired perfusion after myocardial infarction is due to reperfusion-induced δPKC-mediated myocardial damage. Cardiovasc. Res.73, 699–709 (2007). CASPubMed Google Scholar
Ferreira, J. C., Mochly-Rosen, D. & Boutjdir, M. Regulation of cardiac excitability by protein kinase C isozymes. Front. Biosci.4, 532–546 (2012). Google Scholar
Inagaki, K., Koyanagi, T., Berry, N. C., Sun, L. & Mochly-Rosen, D. Pharmacological inhibition of ɛ-protein kinase C attenuates cardiac fibrosis and dysfunction in hypertension-induced heart failure. Hypertension51, 1565–1569 (2008). CASPubMed Google Scholar
Braz, J. C. et al. PKC-α regulates cardiac contractility and propensity toward heart failure. Nature Med.10, 248–254 (2004). CASPubMed Google Scholar
Braun, M. U. & Mochly-Rosen, D. Opposing effects of δ- and ζ-protein kinase C isozymes on cardiac fibroblast proliferation: use of isozyme-selective inhibitors. J. Mol. Cell. Cardiol.35, 895–903 (2003). CASPubMed Google Scholar
Liu, Q. & Molkentin, J. D. Protein kinase Cα as a heart failure therapeutic target. J. Mol. Cell. Cardiol.51, 474–478 (2011). CASPubMed Google Scholar
Hoyt, R. E. & Bowling, L. S. Reducing readmissions for congestive heart failure. Am. Fam. Physician63, 1593–1598 (2001). CASPubMed Google Scholar
Simonis, G. et al. Protein kinase C in the human heart: differential regulation of the isoforms in aortic stenosis or dilated cardiomyopathy. Mol. Cell. Biochem.305, 103–111 (2007). CASPubMed Google Scholar
Bowman, J. C. et al. Expression of protein kinase Cβ in the heart causes hypertrophy in adult mice and sudden death in neonates. J. Clin. Invest.100, 2189–2195 (1997). CASPubMedPubMed Central Google Scholar
Hambleton, M. et al. Pharmacological- and gene therapy-based inhibition of protein kinase Cα/β enhances cardiac contractility and attenuates heart failure. Circulation114, 574–582 (2006). CASPubMedPubMed Central Google Scholar
Huang, L. et al. Increased contractility and altered Ca2+ transients of mouse heart myocytes conditionally expressing PKCβ. Am. J. Physiol. Cell Physiol.280, C1114–C1120 (2001). CASPubMed Google Scholar
Roman, B. B., Geenen, D. L., Leitges, M. & Buttrick, P. M. PKC-β is not necessary for cardiac hypertrophy. Am. J. Physiol. Heart Circ. Physiol.280, H2264–H2270 (2001). CASPubMed Google Scholar
Takeishi, Y. et al. In vivo phosphorylation of cardiac troponin I by protein kinase Cβ2 decreases cardiomyocyte calcium responsiveness and contractility in transgenic mouse hearts. J. Clin. Invest.102, 72–78 (1998). CASPubMedPubMed Central Google Scholar
Ferreira, J. C., Boer, B. N., Grinberg, M., Brum, P. C. & Mochly-Rosen, D. Protein quality control disruption by PKCβII in heart failure; rescue by the selective PKCβII inhibitor, βIIV5-3. PLoS ONE7, e33175 (2012). CASPubMedPubMed Central Google Scholar
Connelly, K. A. et al. Inhibition of protein kinase C-β by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy. Circ. Heart Fail.2, 129–137 (2009). CASPubMed Google Scholar
Ding, R. Q., Tsao, J., Chai, H., Mochly-Rosen, D. & Zhou, W. Therapeutic potential for protein kinase C inhibitor in vascular restenosis. J. Cardiovasc. Pharmacol. Ther.16, 160–167 (2011). CASPubMed Google Scholar
Deuse, T. et al. Sustained inhibition of epsilon protein kinase C inhibits vascular restenosis after balloon injury and stenting. Circulation122, S170–S178 (2010). CASPubMed Google Scholar
Griner, E. M. & Kazanietz, M. G. Protein kinase C and other diacylglycerol effectors in cancer. Nature Rev. Cancer7, 281–294 (2007). CAS Google Scholar
Blumberg, P. M., Delclos, K. B., Dunphy, W. G. & Jaken, S. Specific binding of phorbol ester tumor promoters to mouse tissues and cultured cells. Carcinog. Compr. Surv.7, 519–535 (1982). CASPubMed Google Scholar
Kheifets, V., Bright, R., Inagaki, K., Schechtman, D. & Mochly-Rosen, D. Protein kinase Cδ (δPKC)-annexin V interaction: a required step in δPKC translocation and function. J. Biol. Chem.281, 23218–23226 (2006). CASPubMed Google Scholar
Toker, A. et al. Multiple isoforms of a protein kinase C inhibitor (KCIP-1/14-3-3) from sheep brain — amino acid sequence of phosphorylated forms. Eur. J. Biochem.206, 453–461 (1992). CASPubMed Google Scholar
Gold, M. G. et al. Architecture and dynamics of an A-kinase anchoring protein 79 (AKAP79) signaling complex. Proc. Natl Acad. Sci. USA108, 6426–6431 (2011). CASPubMedPubMed Central Google Scholar
Klauck, T. M. et al. Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein. Science271, 1589–1592 (1996). CASPubMed Google Scholar
Chapline, C. et al. A major, transformation-sensitive PKC-binding protein is also a PKC substrate involved in cytoskeletal remodeling. J. Biol. Chem.273, 19482–19489 (1998). CASPubMed Google Scholar
Mochly-Rosen, D., Khaner, H., Lopez, J. & Smith, B. L. Intracellular receptors for activated protein kinase C. Identification of a binding site for the enzyme. J. Biol. Chem.266, 14866–14868 (1991). This paper describes the first rationally designed peptide inhibitor of PKC localization. CASPubMed Google Scholar
Ron, D., Luo, J. & Mochly-Rosen, D. C2 region-derived peptides inhibit translocation and function of β protein kinase C in vivo. J. Biol. Chem.270, 24180–24187 (1995). CASPubMed Google Scholar
House, C. & Kemp, B. E. Protein kinase C contains a pseudosubstrate prototope in its regulatory domain. Science238, 1726–1728 (1987). This is the first description of a peptide inhibitor of PKC that acts as a competitive inhibitor of the substrate phosphorylation site. CASPubMed Google Scholar
Ron, D. & Mochly-Rosen, D. An autoregulatory region in protein kinase C: the pseudoanchoring site. Proc. Natl Acad. Sci. USA92, 492–496 (1995). CASPubMedPubMed Central Google Scholar
Dorn, G. W. et al. Sustained in vivo cardiac protection by a rationally designed peptide that causes ɛ protein kinase C translocation. Proc. Natl Acad. Sci. USA96, 12798–12803 (1999). CASPubMedPubMed Central Google Scholar
Inagaki, K. et al. Inhibition of δ-protein kinase C protects against reperfusion injury of the ischemic heart in vivo. Circulation108, 2304–2307 (2003). CASPubMed Google Scholar
Armstrong, J. S. & Whiteman, M. Measurement of reactive oxygen species in cells and mitochondria. Methods Cell Biol.80, 355–377 (2007). CASPubMed Google Scholar
Murriel, C. L., Churchill, E., Inagaki, K., Szweda, L. I. & Mochly-Rosen, D. Protein kinase Cδ activation induces apoptosis in response to cardiac ischemia and reperfusion damage: a mechanism involving BAD and the mitochondria. J. Biol. Chem.279, 47985–47991 (2004). CASPubMed Google Scholar
Konopatskaya, O. & Poole, A. W. Protein kinase Cα: disease regulator and therapeutic target. Trends Pharmacol. Sci.31, 8–14 (2010). CASPubMedPubMed Central Google Scholar
Gorin, M. A. & Pan, Q. Protein kinase Cɛ: an oncogene and emerging tumor biomarker. Mol. Cancer8, 9 (2009). PubMedPubMed Central Google Scholar
Lee, S. K. et al. Apurinic/apyrimidinic endonuclease 1 inhibits protein kinase C-mediated p66shc phosphorylation and vasoconstriction. Cardiovasc. Res.91, 502–509 (2011). CASPubMedPubMed Central Google Scholar
Standaert, M. L. et al. Effects of knockout of the protein kinase Cβ gene on glucose transport and glucose homeostasis. Endocrinology140, 4470–4477 (1999). CASPubMed Google Scholar
Chen, C. & Mochly-Rosen, D. Opposing effects of δ and ɛPKC in ethanol-induced cardioprotection. J. Mol. Cell. Cardiol.33, 581–585 (2001). CASPubMed Google Scholar
Mochly-Rosen, D. et al. Cardiotrophic effects of protein kinase Cɛ: analysis by in vivo modulation of PKCɛ translocation. Circ. Res.86, 1173–1179 (2000). CASPubMed Google Scholar
Koide, Y. et al. Differential induction of protein kinase C isoforms at the cardiac hypertrophy stage and congestive heart failure stage in Dahl salt-sensitive rats. Hypertens. Res.26, 421–426 (2003). CASPubMed Google Scholar
Limnander, A. et al. STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nature Immunol.12, 425–433 (2011). CAS Google Scholar
Kilpatrick, L. E. et al. Protection against sepsis-induced lung injury by selective inhibition of protein kinase C-δ (δ-PKC). J. Leukoc. Biol.89, 3–10 (2011). CASPubMedPubMed Central Google Scholar
Boschelli, D. H. Small molecule inhibitors of PKCθ as potential antiinflammatory therapeutics. Curr. Top. Med. Chem.9, 640–654 (2009). CASPubMed Google Scholar
Bright, R., Steinberg, G. K. & Mochly-Rosen, D. δPKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo. Brain Res.1144, 146–155 (2007). CASPubMedPubMed Central Google Scholar
Chou, W. H. & Messing, R. O. Hypertensive encephalopathy and the blood–brain barrier: is δPKC a gatekeeper? J. Clin. Invest.118, 17–20 (2008). CASPubMed Google Scholar
Qi, X., Disatnik, M. H., Shen, N., Sobel, R. A. & Mochly-Rosen, D. Aberrant mitochondrial fission in neurons induced by protein kinase Cδ under oxidative stress conditions in vivo. Mol. Biol. Cell22, 256–265 (2011). CASPubMedPubMed Central Google Scholar
Bright, R., Sun, G. H., Yenari, M. A., Steinberg, G. K. & Mochly-Rosen, D. ɛPKC confers acute tolerance to cerebral ischemic reperfusion injury. Neurosci. Lett.441, 120–124 (2008). CASPubMedPubMed Central Google Scholar
Langlois, A. et al. Crucial implication of protein kinase C (PKC)-δ, PKC-ζ, ERK-1/2, and p38 MAPK in migration of human asthmatic eosinophils. J. Leukoc. Biol.85, 656–663 (2009). CASPubMed Google Scholar
Kanthasamy, A. G. et al. A novel peptide inhibitor targeted to caspase-3 cleavage site of a proapoptotic kinase protein kinase Cδ (PKCδ) protects against dopaminergic neuronal degeneration in Parkinson's disease models. Free Radic. Biol. Med.41, 1578–1589 (2006). CASPubMed Google Scholar
Sawada, M., Imamura, K. & Nagatsu, T. Role of cytokines in inflammatory process in Parkinson's disease. J. Neural Transm. Suppl.2006, 373–381 (2006). Google Scholar
Defauw, J. M. et al. Synthesis and protein kinase C inhibitory activities of acyclic balanol analogs that are highly selective for protein kinase C over protein kinase A. J. Med. Chem.39, 5215–5227 (1996). CASPubMed Google Scholar
Swannie, H. C. & Kaye, S. B. Protein kinase C inhibitors. Curr. Oncol. Rep.4, 37–46 (2002). PubMed Google Scholar
Lee, K.-W. et al. Enzastaurin, a protein kinase Cβ inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer. Cancer Res.68, 1916–1926 (2008). CASPubMed Google Scholar
Gray, M. O., Karliner, J. S. & Mochly-Rosen, D. A selective ɛ-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death. J. Biol. Chem.272, 30945–30951 (1997). CASPubMed Google Scholar
Lahn, M., Sundell, K. & Moore, S. Targeting protein kinase C-α (PKC-α) in cancer with the phosphorothioate antisense oligonucleotide aprinocarsen. Ann. NY Acad. Sci.1002, 263–270 (2003). CASPubMed Google Scholar
Goekjian, P. G. & Jirousek, M. R. Protein kinase C inhibitors as novel anticancer drugs. Expert Opin. Investig. Drugs10, 2117–2140 (2001). CASPubMed Google Scholar
Tamaoki, T. Use and specificity of staurosporine, UCN-01, and calphostin C as protein kinase inhibitors. Methods Enzymol.201, 340–347 (1991). CASPubMed Google Scholar
Kraft, A. S., Smith, J. B. & Berkow, R. L. Bryostatin, an activator of the calcium phospholipid-dependent protein kinase, blocks phorbol ester-induced differentiation of human promyelocytic leukemia cells HL-60. Proc. Natl Acad. Sci. USA83, 1334–1338 (1986). CASPubMedPubMed Central Google Scholar
Schwarze, S. R., Ho, A., Vocero-Akbani, A. & Dowdy, S. F. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science285, 1569–1572 (1999). CASPubMed Google Scholar
Qi, X., Inagaki, K., Sobel, R. A. & Mochly-Rosen, D. Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood–brain barrier breakdown in rats. J. Clin. Invest.118, 173–182 (2008). CASPubMed Google Scholar
Kim, J., Thorne, S. H., Sun, L., Huang, B. & Mochly-Rosen, D. Sustained inhibition of PKCα reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model. Oncogene30, 323–333 (2011). CASPubMed Google Scholar
Inagaki, K., Begley, R., Ikeno, F. & Mochly-Rosen, D. Cardioprotection by ɛ-protein kinase C activation from ischemia: continuous delivery and antiarrhythmic effect of an ɛ-protein kinase C-activating peptide. Circulation111, 44–50 (2005). CASPubMed Google Scholar
Drew, B. G. & Kingwell, B. A. Acadesine, an adenosine-regulating agent with the potential for widespread indications. Expert Opin. Pharmacother.9, 2137–2144 (2008). CASPubMed Google Scholar
Zhao, B. et al. Structural basis for Chk1 inhibition by UCN-01. J. Biol. Chem.277, 46609–46615 (2002). CASPubMed Google Scholar