Protein kinase C and other diacylglycerol effectors in cancer (original) (raw)

• Castagna, M. et al. Direct activation of calcium-activated, phospholipid-dependent protein-kinase by tumor-promoting phorbol esters. J. Biol. Chem. 257, 7847–7851 (1982).
  CAS PubMed Google Scholar
• Kikkawa, U., Takai, Y., Tanaka, Y., Miyake, R. & Nishizuka, Y. Protein kinase-C as a possible receptor protein of tumor-promoting phorbol esters. J. Biol. Chem. 258, 1442–1445 (1983).
  Google Scholar
• Leach, K. L., James, M. L. & Blumberg, P. M. Characterization of a specific phorbol ester aporeceptor in mouse-brain cytosol. Proc. Natl Acad. Sci. USA 80, 4208–4212 (1983).
  CAS PubMed PubMed Central Google Scholar
• Kishimoto, A., Takai, Y., Mori, T., Kikkawa, U. & Nishizuka, Y. Activation of calcium and phospholipid-dependent protein-kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover. J. Biol. Chem. 255, 2273–2276 (1980).
  CAS PubMed 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).
  CAS PubMed Google Scholar
• Sharkey, N. A., Leach, K. L. & Blumberg, P. M. Competitive inhibition by diacylglycerol of specific phorbol ester binding. Proc. Natl Acad. Sci. USA 81, 607–610 (1984). This paper was the first to unambiguously show that DAG and phorbol esters bind to the same site on PKC, providing reliable evidence that the phorbol esters function by mimicking the action of DAG.
  CAS PubMed PubMed Central Google Scholar
• Hirai, T. & Chida, K. Protein kinase C ζ (PKCζ): activation mechanisms and cellular functions. J. Biochem. 133, 1–7 (2003).
  CAS PubMed Google Scholar
• Suzuki, A., Akimoto, K. & Ohno, S. Protein kinase C λ/ι (PKCλ/ι): a PKC isotype essential for the development of multicellular organisms. J. Biochem. 133, 9–16 (2003).
  CAS PubMed Google Scholar
• Moscat, J. & Diaz-Meco, M. T. The atypical protein kinase Cs — functional specificity mediated by specific protein adapters. EMBO Rep. 1, 399–403 (2000).
  CAS PubMed PubMed Central Google Scholar
• Newton, A. C. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem. J. 370, 361–371 (2003).
  CAS PubMed PubMed Central Google Scholar
• Parekh, D. B., Ziegler, W. & Parker, P. J. Multiple pathways control protein kinase C phosphorylation. EMBO J. 19, 496–503 (2000). References 10 and 11 are excellent reviews that describe the ways that transphosphorylation or autophosphorylation of PKC isozymes can control maturation and activation.
  CAS PubMed PubMed Central 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).
  CAS PubMed Google Scholar
• Wang, Q. M. J. et al. Differential localization of protein kinase C δ by phorbol esters and related compounds using a fusion protein with green fluorescent protein. J. Biol. Chem. 274, 37233–37239 (1999).
  CAS PubMed Google Scholar
• Jaken, S. & Parker, P. J. Protein kinase C binding partners. Bioessays 22, 245–254 (2000).
  CAS PubMed Google Scholar
• Schechtman, D. & Mochly-Rosen, D. Adaptor proteins in protein kinase C-mediated signal transduction. Oncogene 20, 6339–6347 (2001). This review highlights how PKC interaction with adaptor proteins might dictate specificity by regulating substrate interactions, and therefore serve as a basis for isozyme specificity.
  CAS PubMed Google Scholar
• Colon-Gonzalez, F. & Kazanietz, M. G. C1 domains exposed: from diacylglycerol binding to protein–protein interactions. Biochim. Biophys. Acta 1761, 827–837 (2006).
  CAS PubMed Google Scholar
• Hsiao, W. L. W., Housey, G. M., Johnson, M. D. & Weinstein, I. B. Cells that overproduce protein kinase-C are more susceptible to transformation by an activated H-Ras oncogene. Mol. Cell. Biol. 9, 2641–2647 (1989).
  CAS PubMed PubMed Central Google Scholar
• Lacal, J. C., Fleming, T. P., Warren, B. S., Blumberg, P. M. & Aaronson, S. A. Involvement of functional protein-kinase-C in the mitogenic response to the H-Ras oncogene product. Mol. Cell. Biol. 7, 4146–4149 (1987).
  CAS PubMed PubMed Central Google Scholar
• Wolfman, A. & Macara, I. G. Elevated levels of diacylglycerol and decreased phorbol ester sensitivity in Ras-transformed fibroblasts. Nature 325, 359–361 (1987).
  CAS PubMed Google Scholar
• Dotto, G. P., Parada, L. F. & Weinberg, R. A. Specific growth-response of Ras-transformed embryo fibroblasts to tumor promoters. Nature 318, 472–475 (1985).
  CAS PubMed Google Scholar
• Barr, L. F. et al. c-Myc gene-induced alterations in protein-kinase-C expression — a possible mechanism facilitating Myc–Ras gene complementation. Cancer Res. 51, 5514–5519 (1991).
  CAS PubMed Google Scholar
• Borner, C., Ueffing, M., Jaken, S., Parker, P. J. & Weinstein, I. B. 2 closely-related isoforms of protein-kinase-C produce reciprocal effects on the growth of rat fibroblasts — possible molecular mechanisms. J. Biol. Chem. 270, 78–86 (1995).
  CAS PubMed Google Scholar
• Han, E. K. H., Cacace, A. M., Sgambato, A. & Weinstein, I. B. Altered expression of cyclins and c-Fos in R6 cells that overproduce Pkc-ε. Carcinogenesis 16, 2423–2428 (1995).
  CAS PubMed Google Scholar
• Cacace, A. M. et al. PKCε functions as an oncogene by enhancing activation of the Raf kinase. Oncogene 13, 2517–2526 (1996).
  CAS PubMed Google Scholar
• Mischak, H. et al. Overexpression of protein kinase-C-δ and kinase-ε in NIH 3T3 cells induces opposite effects on growth, morphology, anchorage dependence, and tumorigenicity. J. Biol. Chem. 268, 6090–6096 (1993).
  CAS PubMed Google Scholar
• Pan, Q., Bao, L. W., Teknos, T. N. & Merajver, S. D. Targeted disruption of protein kinase C ε reduces cell invasion and motility through inactivation of RhoA and RhoC GTPases in head and neck squamous cell carcinoma. Cancer Res. 66, 9379–9384 (2006).
  CAS PubMed PubMed Central Google Scholar
• Tachado, S. D. et al. Regulation of tumor invasion and metastasis in protein kinase C ε-transformed NIH3T3 fibroblasts. J. Cell. Biochem. 85, 785–797 (2002).
  CAS PubMed Google Scholar
• Jackson, D. N. & Foster, D. A. The enigmatic protein kinase C δ: complex roles in cell proliferatin and survival. FASEB J. 18, 627–636 (2004).
  CAS PubMed Google Scholar
• Heit, I. et al. Involvement of protein kinase C δ in contact-dependent inhibition of growth in human and murine fibroblasts. Oncogene 20, 5143–5154 (2001).
  CAS PubMed Google Scholar
• Hornia, A. et al. Antagonistic effects of protein kinase C α and δ on both transformation and phospholipase D activity mediated by the epidermal growth factor receptor. Mol. Cell. Biol. 19, 7672–7680 (1999).
  CAS PubMed PubMed Central Google Scholar
• Perletti, G. P., Marras, E., Concari, P., Piccinini, F. & Tashjian, A. H. PKCδ acts as a growth and tumor suppressor in rat colonic epithelial cells. Oncogene 18, 1251–1256 (1999).
  CAS PubMed Google Scholar
• Lu, Z. M. et al. Tumor promotion by depleting cells of protein kinase C δ. Mol. Cell. Biol. 17, 3418–3428 (1997). This paper demonstrates that phorbol 12-myristate 13-acetate induces transformation-related phenotypes in a cell line overexpressing-Src, and provides strong evidence that the tumour-promoter activity of phorbol esters might be due to downregulation of a growth inhibitory PKC (PKCδ).
  CAS PubMed PubMed Central Google Scholar
• Hennings, H. et al. Bryostatin-1, an activator of protein-kinase-C, inhibits tumor promotion by phorbol esters in sencar mouse skin. Carcinogenesis 8, 1343–1346 (1987).
  CAS PubMed 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).
  CAS PubMed Google Scholar
• Riobo, N. A., Haines, G. M. & Emerson, C. P. Protein kinase C-δ and mitogen-activated protein/extracellular signal-regulated kinase-1 control GLI activation in hedgehog signaling. Cancer Res. 66, 839–845 (2006).
  CAS PubMed Google Scholar
• Kinoshita, N., Iioka, H., Miyakoshi, A. & Ueno, N. PKCδ is essential for Dishevelled function in a noncanonical Wnt pathway that regulates Xenopus convergent extension movements. Genes Dev. 17, 1663–1676 (2003).
  CAS PubMed PubMed Central Google Scholar
• Jiang, X. H. et al. Antisense targeting protein kinase C α and β(1) inhibits gastric carcinogenesis. Cancer Res. 64, 5787–5794 (2004).
  CAS PubMed Google Scholar
• Wheeler, D. L., Ness, K. J., Oberley, T. D. & Verma, A. K. Protein kinase C ε is linked to 12-_O_-tetradecanoylphorbol-13-acetate-induced tumor necrosis factor-α ectodomain shedding and the development of metastatic squamous cell carcinoma in protein kinase C ε transgenic mice. Cancer Res. 63, 6547–6555 (2003).
  CAS PubMed Google Scholar
• Reddig, P. J. et al. Transgenic mice overexpressing protein kinase C ε in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion. Cancer Res. 60, 595–602 (2000). This paper provides in vivo evidence for a pro-tumorigenic role of PKCε in a transgenic mouse model, and shows that elevated levels of PKCε in the epidermis lead to the development of carcinomas independently of papilloma formation.
  CAS PubMed Google Scholar
• Reddig, P. J. et al. Transgenic mice overexpressing protein kinase C δ in the epidermis are resistant to skin tumor promotion by 12-_O_-tetradecanoylphorbol-13-acetate. Cancer Res. 59, 5710–5718 (1999).
  CAS PubMed Google Scholar
• Gokmen-Polar, Y., Murray, N. R., Velasco, M. A., Gatalica, Z. & Fields, A. P. Elevated protein kinase C βII is an early promotive event in colon carcinogenesis. Cancer Res. 61, 1375–1381 (2001).
  CAS PubMed Google Scholar
• Murray, N. R. et al. Overexpression of protein kinase C βII induces colonic hyperproliferation and increased sensitivity to colon carcinogenesis. J. Cell Biol. 145, 699–711 (1999). Transgenic mice overexpressing PKCβII in the intestinal epithelium show increased proliferation and susceptibility to azoxymethane-induced aberrant crypt foci, as well as activation of the APC–β-catenin signalling pathway.
  CAS PubMed PubMed Central Google Scholar
• Yu, W. S. et al. Role of cyclooxygenase 2 in protein kinase C βII-mediated colon carcinogenesis. J. Biol. Chem. 278, 11167–11174 (2003).
  CAS PubMed Google Scholar
• Zhang, J., Anastasiadis, P. Z., Liu, Y., Thompson, E. A. & Fields, A. P. Protein kinase C (PKC) β II induces cell invasion through a Ras/Mek-, PKCι/Rac1-dependent signaling pathway. J. Biol. Chem. 279, 22118–22123 (2004).
  CAS PubMed Google Scholar
• Sledge, G. W. & Gokmen-Polar, Y. Protein kinase C-β as a therapeutic target in breast cancer. Semin. Oncol. 33, S15–S18 (2006).
  CAS PubMed Google Scholar
• Graff, J. R. et al. The protein kinase C β-selective inhibitor, enzastaurin (LY317615. HCI), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res. 65, 7462–7469 (2005).
  CAS PubMed Google Scholar
• Oberschmidt O. et al. Enzastaurin and pemetrexed exert synergistic antitumor activity in thyroid cancer cell lines in vitro. Int. J. Clin. Pharmacol. Ther. 43, 603–604 (2005).
  CAS PubMed Google Scholar
• Querfeld, C. et al. The selective protein kinase C β inhibitor enzastaurin induces apoptosis in cutaneous T-cell lymphoma cell lines through the AKT pathway. J. Invest. Dermatol. 126, 1641–1647 (2006).
  CAS PubMed Google Scholar
• Alvaro, V. et al. Invasive human pituitary-tumors express a point-mutated α-protein kinase-C. J. Clin. Endocrinol. Metabol. 77, 1125–1129 (1993).
  CAS Google Scholar
• Prevostel, C., Martin, A., Alvaro, V., Jaffiol, C. & Joubert, D. Protein kinase C α and tumorigenesis of the endocrine gland. Hormone Res. 47, 140–144 (1997).
  CAS PubMed Google Scholar
• Zhu, Y. M. et al. The PKCα-D294G mutant found in pituitary and thyroid tumors fails to transduce extracellular signals. Cancer Res. 65, 4520–4524 (2005).
  CAS PubMed Google Scholar
• Knauf, J. A. et al. Involvement of protein kinase C ε (PKCε) in thyroid cell death — a truncated chimeric PKCε cloned from a thyroid cancer cell line protects thyroid cells from apoptosis. J. Biol. Chem. 274, 23414–23425 (1999).
  CAS PubMed Google Scholar
• Black, J. D. Protein kinase C-mediated regulation of the cell cycle. Front. Biosci. 5, D406–D423 (2000).
  CAS PubMed Google Scholar
• Gavrielides, M. V., Frijhoff, A. F., Conti, C. J. & Kazanietz, M. G. Protein kinase C and prostate carcinogenesis: targeting the cell cycle and apoptotic mechanisms. Curr. Drug Targets 5, 431–443 (2004).
  CAS PubMed Google Scholar
• Detjen, K. M. et al. Activation of protein kinase Cα inhibits growth of pancreatic cancer cells via p21_cip_-mediated G1 arrest. J. Cell Sci. 113, 3025–3035 (2000).
  CAS PubMed Google Scholar
• Frey, M. R. et al. Protein kinase C isozyme-mediated cell cycle arrest involves induction of p21_waf1/cip1_ and p27_kip1_ and hypophosphorylation of the retinoblastoma protein in intestinal epithelial cells. J. Biol. Chem. 272, 9424–9435 (1997).
  CAS PubMed Google Scholar
• Slosberg, E. D. et al. The α isoform of protein kinase C mediates phorbol ester-induced growth inhibition and p21_cip1_ induction in HC11 mammary epithelial cells. Oncogene 18, 6658–6666 (1999).
  CAS PubMed Google Scholar
• Clark, J. A. et al. Involvement of the ERK signaling cascade in protein kinase C-mediated cell cycle arrest in intestinal epithelial cells. J. Biol. Chem. 279, 9233–9247 (2004).
  CAS PubMed Google Scholar
• Frey, M. R. et al. Protein kinase C signaling mediates a program of cell cycle withdrawal in the intestinal epithelium. J. Cell Biol. 151, 763–777 (2000). This work points to a growth-inhibitory role for PKCα in intestinal epithelial cells and proposes mechanisms through which cell-cycle inhibition occurs by regulation of cyclins and CDK inhibitors.
  CAS PubMed PubMed Central Google Scholar
• Oster, H. & Leitges, M. Protein kinase Cα but not PKCζ suppresses intestinal tumor formation in Apc_Min/+_ mice. Cancer Res. 66, 6955–6963 (2006).
  CAS PubMed Google Scholar
• Nakagawa, M. et al. Phorbol ester-induced G1 phase arrest selectively mediated by protein kinase Cδ-dependent induction of p21. J. Biol. Chem. 280, 33926–33934 (2005).
  CAS PubMed Google Scholar
• Miyamoto, A. et al. Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ. Nature 416, 865–869 (2002).
  CAS PubMed Google Scholar
• Czifra, G. et al. Insulin-like growth factor-I-coupled mitogenic signaling in primary cultured human skeletal muscle cells and in C2C12 myoblasts. A central role of protein kinase Cδ. Cell. Signal. 18, 1461–1472 (2006).
  CAS PubMed Google Scholar
• Walker. J. L., Castagnino P., Chung. B. M., Kazanietz. M. G. & Assoian. R. K. Post-transcriptional destabilization of p21_cip1_ by protein kinase C in fibroblasts. J. Biol. Chem. 281, 38127–38132 (2006).
  CAS PubMed Google Scholar
• Grossoni, V. C. et al. Protein kinase C δ enhances proliferation and survival of normal murine mammary cells. Mol. Carcinogen. 11 Jan 2007 (doi 10.1002/mc20287).
• Steinberg, S. F. Distinctive activation mechanisms and functions for protein kinase Cδ. Biochem. J. 384, 449–459 (2004).
  CAS PubMed PubMed Central Google Scholar
• Gubina, E., Rinaudo, M. S., Szallasi, Z., Blumberg, P. M. & Mufson, R. A. Overexpression of protein kinase C isoform ε but not δ in human interleukin-3-dependent cells suppresses apoptosis and induces BCL-2 expression. Blood 91, 823–829 (1998).
  CAS PubMed Google Scholar
• Okhrimenko, H. et al. Protein kinase C-ε: regulates the apoptosis and survival of glioma cells. Cancer Res. 65, 7301–7309 (2005).
  CAS PubMed PubMed Central Google Scholar
• Gillespie, S., Zhang, X. D. & Hersey, P. Variable expression of protein kinase C ε in human melanoma cells regulates sensitivity to TRAIL-induced apoptosis. Mol. Cancer Ther. 4, 668–676 (2005).
  CAS PubMed Google Scholar
• Lu, D. M., Huang, J. & Basu, A. Protein kinase C ε activates protein kinase B/Akt via DNA-PK to protect against tumor necrosis factor-α-induced cell death. J. Biol. Chem. 281, 22799–22807 (2006).
  CAS PubMed Google Scholar
• Pardo, O. E. et al. FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCε, B-Raf and S6K2. EMBO J. 25, 3078–3088 (2006).
  CAS PubMed PubMed Central Google Scholar
• Ding, L., Wang, H. M., Lang, W. H. & Xiao, L. Protein kinase C-ε promotes survival of lung cancer cells by suppressing apoptosis through dysregulation of the mitochondrial caspase pathway. J. Biol. Chem. 277, 35305–35313 (2002).
  CAS PubMed Google Scholar
• Basu, A. & Weixel, K. M. Comparison of protein-kinase-C activity and isoform expression in cisplatin-sensitive and cisplatin-resistant ovarian-carcinoma cells. Int. J. Cancer 62, 457–460 (1995).
  CAS PubMed Google Scholar
• Emoto, Y. et al. Proteolytic activation of protein kinase C δ by an ICE-like protease in apoptotic cells. EMBO J. 14, 6148–6156 (1995). This was the first demonstration that apoptotic stimuli lead to the proteolytic cleavage of a PKC. The constitutively active PKCδ catalytic fragment generated by caspase activation was later found to have a significant role in programmed cell death by ionizing radiation or DNA-damaging agents.
  CAS PubMed PubMed Central Google Scholar
• Denning, M. F., Wang, Y. H., Nickoloff, B. J. & Wrone-Smith, T. Protein kinase C δ is activated by caspase-dependent proteolysis during ultraviolet radiation-induced apoptosis of human keratinocytes. J. Biol. Chem. 273, 29995–30002 (1998).
  CAS PubMed Google Scholar
• Reyland, M. E., Anderson, S. M., Matassa, A. A., Barzen, K. A. & Quissell, D. O. Protein kinase C δ is essential for etoposide-induced apoptosis in salivary gland acinar cells. J. Biol. Chem. 274, 19115–19123 (1999).
  CAS PubMed Google Scholar
• Persaud, S. D., Hoang, V., Huang, J. & Basu, A. Involvement of proteolytic activation of PKC δ in cisplatin-induced apoptosis in human small cell lung cancer H69 cells. Int. J. Oncol. 27, 149–154 (2005).
  CAS PubMed Google Scholar
• Humphries, M. J. et al. Suppression of apoptosis in the protein kinase C δ null mouse in vivo. J. Biol. Chem. 281, 9728–9737 (2006). This work shows that loss of PKCδ in mice is protective against gamma-radiation-induced apoptosis and that PKCδ function is needed for apoptosis in vivo . PKCδ is needed for JNK activation following DNA damage.
  CAS PubMed Google Scholar
• Li, L. W., Lorenzo, P. S., Bogi, K., Blumberg, P. M. & Yuspa, S. H. Protein kinase C δ targets mitochondria, alters mitochondrial membrane potential, and induces apoptosis in normal and neoplastic keratinocytes when overexpressed by an adenoviral vector. Mol. Cell. Biol. 19, 8547–8558 (1999).
  CAS PubMed PubMed Central Google Scholar
• Majumder, P. K. et al. Mitochondrial translocation of protein kinase C δ in phorbol ester-induced cytochrome C release and apoptosis. J. Biol. Chem. 275, 21793–21796 (2000).
  CAS PubMed Google Scholar
• Denning, M. F. et al. Caspase activation and disruption of mitochondrial membrane potential during UV radiation-induced apoptosis of human keratinocytes requires activation of protein kinase C. Cell Death Differ. 9, 40–52 (2002).
  CAS PubMed Google Scholar
• DeVries, T. A., Neville, M. C. & Reyland, M. E. Nuclear import of PKCδ is required for apoptosis: identification of a novel nuclear import sequence. EMBO J. 21, 6050–6060 (2002).
  CAS PubMed PubMed Central Google Scholar
• Kaul, S. et al. Tyrosine phosphorylation regulates the proteolytic activation of protein kinase C δ in dopaminergic neuronal cells. J. Biol. Chem. 280, 28721–28730 (2005).
  CAS PubMed Google Scholar
• Blass, M., Kronfeld, I., Kazimirsky, G., Blumberg, P. M. & Brodie, C. Tyrosine phosphorylation of protein kinase C δ is essential for its apoptotic effect in response to etoposide. Mol. Cell. Biol. 22, 182–195 (2002). This paper shows that PKCδ, unlike most PKCs, can be regulated by tyrosine phosphorylation, and that this event is required for apoptosis induced by DNA-damaging agents. Relevant tyrosine-phosphorylation sites have been identified.
  CAS PubMed PubMed Central Google Scholar
• Yuan, Z. M. et al. Activation of protein kinase C δ by the c-Abl tyrosine kinase in response to ionizing radiation. Oncogene 16, 1643–1648 (1998).
  CAS PubMed Google Scholar
• Cross, T. et al. PKC-δ is an apoptotic lamin kinase. Oncogene 19, 2331–2337 (2000).
  CAS PubMed Google Scholar
• Frasch, S. C. et al. Regulation of phospholipid scramblase activity during apoptosis and cell activation by protein kinase C δ. J. Biol. Chem. 275, 23065–23073 (2000).
  CAS PubMed Google Scholar
• Bharti, A. et al. Inactivation of DNA-dependent protein kinase by protein kinase C δ: implications for apoptosis. Mol. Cell. Biol. 18, 6719–6728 (1998).
  CAS PubMed PubMed Central Google Scholar
• Yoshida, K. et al. Protein kinase C δ activates topoisomerase IIα to induce apoptotic cell death in response to DNA damage. Mol. Cell. Biol. 26, 3414–3431 (2006).
  CAS PubMed PubMed Central Google Scholar
• Gonzalez-Guerrico, A. M. & Kazanietz, M. G. Phorbol ester-induced apoptosis in prostate cancer cells via autocrine activation of the extrinsic apoptotic cascade — a key role for protein kinase C δ. J. Biol. Chem. 280, 38982–38991 (2005). This paper shows that the apoptotic effect of a PKC is mediated by an autocrine loop that involves activation of the extrinsic apoptotic pathway.
  CAS PubMed Google Scholar
• Tanaka, Y., Gavrielides, M. V., Mitsuuchi, Y., Fujii, T. & Kazanietz, M. G. Protein kinase C promotes apoptosis in LNCaP prostate cancer cells through activation of p38 MAPK and inhibition of the Akt survival pathway. J. Biol. Chem. 278, 33753–33762 (2003).
  CAS PubMed Google Scholar
• Ways, D. K. et al. Mcf-7 breast-cancer cells transfected with protein-kinase C-α exhibit altered expression of other protein-kinase-C isoforms and display a more aggressive neoplastic phenotype. J. Clin. Invest. 95, 1906–1915 (1995).
  CAS PubMed PubMed Central Google Scholar
• Tan, M., Li, P., Sun, M., Yin, G. & Yu, D. Upregulation and activation of PKCα by ERBB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors. Oncogene 25, 3286–3295 (2006).
  CAS PubMed Google Scholar
• Pan, Q. et al. Protein kinase C ε is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy. Cancer Res. 65, 8366–8371 (2005).
  CAS PubMed Google Scholar
• Jackson, D. et al. Suppression of cell migration by protein kinase C δ. Oncogene 24, 3067–3072 (2005).
  CAS PubMed Google Scholar
• Ng, T. et al. PKCα regulates β1 integrin-dependent cell motility through association and control of integrin traffic. EMBO J. 18, 3909–3923 (1999). PKCα regulates motility through the control of cell-surface expression and recycling of β1-integrin.
  CAS PubMed PubMed Central Google Scholar
• Parsons, M. et al. Site-directed perturbation of protein kinase C-integrin interaction blocks carcinoma cell chemotaxis. Mol. Cell. Biol. 22, 5897–5911 (2002).
  CAS PubMed PubMed Central Google Scholar
• Liu, J. F., Crepin, M., Liu, J. M., Barritault, D. & Ledoux, D. FGF-2 and TPA induce matrix metalloproteinase-9 secretion in MCF-7 cells through PKC activation of the Ras/ERK pathway. Biochem. Biophys. Res. Commun. 293, 1174–1182 (2002).
  CAS PubMed Google Scholar
• Sliva, D., English, D., Lyons, D. & Lloyd, F. P. Protein kinase C induces motility of breast cancers by upregulating secretion of urokinase-type plasminogen activator through activation of AP-1 and NF-κB. Biochem. Biophys. Res. Commun. 290, 552–557 (2002).
  CAS PubMed Google Scholar
• Urtreger, A. J., Grossoni, V. C., Falbo, K. B., Kazanietz, M. G. & Joffe, E. Atypical protein kinase C-ζ modulates clonogenicity, motility, and secretion of proteolytic enzymes in murine mammary cells. Mol. Carcinog. 42, 29–39 (2005).
  CAS PubMed Google Scholar
• Wellner, M. et al. The proliferative effect of vascular endothelial growth factor requires protein kinase C-α and protein kinase C-ζ. Arterioscler. Thromb. Vasc. Biol. 19, 178–185 (1999).
  CAS PubMed Google Scholar
• Wu, L. W. et al. Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation. J. Biol. Chem. 275, 5096–5103 (2000).
  CAS PubMed Google Scholar
• Xia, P. et al. Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J. Clin. Invest. 98, 2018–2026 (1996).
  CAS PubMed PubMed Central Google Scholar
• Suzuma, K. et al. Characterization of protein kinase C β isoform's action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization. Proc. Natl Acad. Sci. USA 99, 721–726 (2002).
  CAS PubMed PubMed Central Google Scholar
• Takahashi, T., Ueno, H. & Shibuya, M. VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 18, 2221–2230 (1999).
  CAS PubMed Google Scholar
• Wong, C. & Jin, Z. G. Protein kinase C-dependent protein kinase D activation modulates ERK signal pathway and endothelial cell proliferation by vascular endothelial growth factor. J. Biol. Chem. 280, 33262–33269 (2005).
  CAS PubMed Google Scholar
• Yoshiji, H. et al. Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis. Cancer Res. 59, 4413–4418 (1999).
  CAS PubMed Google Scholar
• Teicher, B. A. et al. Antiangiogenic and antitumor effects of a protein kinase C β inhibitor in human HT-29 colon carcinoma and human CaKi1 renal cell carcinoma xenografts. Anticancer Res. 21, 3175–3184 (2001).
  CAS PubMed Google Scholar
• Teicher, B. A. et al. Antiangiogenic and antitumor effects of a protein kinase C β inhibitor in murine Lewis lung carcinoma and human Calu-6 non-small-cell lung carcinoma xenografts. Cancer Chemother. Pharmacol. 48, 473–480 (2001).
  CAS PubMed Google Scholar
• Teicher, B. A., Menon, K., Alvarez, E., Shih, C. & Faul, M. M. Antiangiogenic and antitumor effects of a protein kinase C β inhibitor in human breast cancer and ovarian cancer xenografts. Invest. New Drugs 20, 241–251 (2002).
  CAS PubMed Google Scholar
• Teicher, B. A., Menon, K., Alvarez, E., Shih, P. L. C. & Faul, M. M. Antiangiogenic and antitumor effects of a protein kinase C β inhibitor in human hepatocellular and gastric cancer xenografts. In Vivo 15, 185–193 (2001).
  CAS PubMed Google Scholar
• Wang, Q. M. J. PKD at the crossroads of DAG and PKC signaling. Trends Pharmacol. Sci. 27, 317–323 (2006).
  CAS PubMed Google Scholar
• Storz, P., Doppler, H. & Toker, A. Protein kinase C δ selectively regulates protein kinase D-dependent activation of NF-κB in oxidative stress signaling. Mol. Cell. Biol. 24, 2614–2626 (2004).
  CAS PubMed PubMed Central Google Scholar
• Storz P, T. A. Protein kinase D mediates a stress-induced NF-κB activation and survival pathway. EMBO J. 22, 109–120 (2003).
  PubMed PubMed Central Google Scholar
• Mihailovic, T. et al. Protein kinase D2 mediates activation of nuclear factor κB by Bcr-Abl in Bcr-Abl(+) human myeloid leukemia cells. Cancer Res. 64, 8939–8944 (2004).
  CAS PubMed Google Scholar
• Shindo, M. et al. Synthesis and phorbol ester binding of the cysteine-rich domains of diacylglycerol kinase (DGK) isozymes — DGKγ and DGKγ are new targets of tumor-promoting phorbol esters. J. Biol. Chem. 278, 18448–18454 (2003).
  CAS PubMed Google Scholar
• Luo, B., Regier, D. S., Prescott, S. M. & Topham, M. K. Diacylglycerol kinases. Cell. Signal. 16, 983–989 (2004).
  CAS PubMed Google Scholar
• Bacchiocchi, R. et al. Activation of α-diacylglycerol kinase is critical for the mitogenic properties of anaplastic lymphoma kinase. Blood 106, 2175–2182 (2005).
  CAS PubMed Google Scholar
• Crotty, T. et al. Diacylglycerol kinase δ regulates protein kinase C and epidermal growth factor receptor signaling. Proc. Natl Acad. Sci. USA 103, 15485–15490 (2006).
  CAS PubMed PubMed Central Google Scholar
• Macdonald, M. L., Mack, K. F., Richardson, C. N. & Glomset, J. A. Regulation of diacylglycerol kinase reaction in Swiss 3t3-cells. Increased phosphorylation of endogenous diacylglycerol and decreased phosphorylation of didecanoylglycerol in response to platelet-derived growth-factor. J. Biol. Chem. 263, 1575–1583 (1988).
  CAS PubMed Google Scholar
• Tsushima, S. et al. Diacylglycerol kinase γ serves as an upstream suppressor of Rac1 and lamellipodium formation. J. Biol. Chem. 279, 28603–28613 (2004).
  CAS PubMed Google Scholar
• Stone, J. C. Regulation of Ras in lymphocytes: get a GRP. Biochem. Soc. Trans. 34, 858–861 (2006).
  CAS PubMed Google Scholar
• Ebinu, J. O. et al. RasGRP, a Ras guanyl nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Science 280, 1082–1086 (1998).
  CAS PubMed Google Scholar
• Irie, K., Masuda, A., Shindo, M., Nakagawa, Y. & Ohigashi, H. Tumor promoter binding of the protein kinase CC1 homology domain peptides of RasGRPs, chimaerins, and Unc13s. Bioorg. Med. Chem. 12, 4575–4583 (2004).
  CAS PubMed Google Scholar
• Zheng, Y. et al. Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells. Blood 105, 3648–3654 (2005).
  CAS PubMed Google Scholar
• Bivona, T. G. et al. Phospholipase C γ activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424, 694–698 (2003).
  CAS PubMed Google Scholar
• Ebinu, J. O. et al. RasGRP links T-cell receptor signaling to Ras. Blood 95, 3199–3203 (2000).
  CAS PubMed Google Scholar
• Dower, N. A. et al. RasGRP essential for mouse thymocyte differentiation and TCR signaling. Nature Immunol. 1, 317–321 (2000).
  CAS Google Scholar
• Norment, A. M. et al. Transgenic expression of RasGRP1 induces the maturation of double-negative thymocytes and enhances the production of CD8 single-positive thymocytes. J. Immunol. 170, 1141–1149 (2003).
  CAS PubMed Google Scholar
• Klinger, M. B., Guilbault, B., Goulding, R. E. & Kay, R. J. Deregulated expression of RasGRP1 initiates thymic lymphomagenesis independently of T-cell receptors. Oncogene 24, 2695–2704 (2005). This paper links the DAG receptor RasGRP1 to cancer, as transgenic RasGRP1 mice develop T-cell malignancies.
  CAS PubMed Google Scholar
• Kim, R. et al. Genome-based identification of cancer genes by proviral tagging in mouse retrovirus-induced T-cell lymphornas. J. Virol. 77, 2056–2062 (2003).
  CAS PubMed PubMed Central Google Scholar
• Coughlin, J. J., Stang, S. L., Dower, N. A. & Stone, J. C. RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor–Ras signaling. J. Immunol. 175, 7179–7184 (2005).
  CAS PubMed Google Scholar
• Yang, Y. et al. RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demonstration of the importance of RasGRP4 in mast cell development and function. J. Biol. Chem. 277, 25756–25774 (2002).
  CAS PubMed Google Scholar
• Roberts, D. M. et al. A vascular gene trap screen defines RasGRP3 as an angiogenesis-regulated gene required for the endothelial response to phorbol esters. Mol. Cell. Biol. 24, 10515–10528 (2004).
  CAS PubMed PubMed Central Google Scholar
• Rambaratsingh, R. A., Stone, J. C., Blumberg, P. M. & Lorenzo, P. S. RasGRP1 represents a novel non-protein kinase C phorbol ester signaling pathway in mouse epidermal keratinocytes. J. Biol. Chem. 278, 52792–52801 (2003).
  CAS PubMed Google Scholar
• Oki-Idouchi, C. E. & Lorenzo, P. S. Transgenic overexpression of RasGRP1 in mouse epidermis results in spontaneous tumors of the skin. Cancer Res. 67, 276–280 (2007).
  CAS PubMed PubMed Central Google Scholar
• Hall, C. et al. Novel human-brain cDNA-encoding a 34,000 Mr protein N-chimaerin, related to both the regulatory domain of protein kinase-C and BCR, the product of the breakpoint cluster region gene. J. Mol. Biol. 211, 11–16 (1990).
  CAS PubMed Google Scholar
• Hall, C. et al. α2-chimaerin, a Cdc42/Rac1 regulator, is selectively expressed in the rat embryonic nervous system and is involved in neuritogenesis in N1E-115 neuroblastoma cells. J. Neurosci. 21, 5191–5202 (2001).
  CAS PubMed PubMed Central Google Scholar
• Leskow, F. C., Holloway, B. A., Wang, H. B., Mullins, M. C. & Kazanietz, M. G. The zebrafish homologue of mammalian chimerin Rac-GAPs is implicated in epiboly progression during development. Proc. Natl Acad. Sci. USA 103, 5373–5378 (2006).
  CAS PubMed PubMed Central Google Scholar
• Menna, P. L. et al. Inhibition of aggressiveness of metastatic mouse mammary carcinoma cells by the β2-chimaerin GAP domain. Cancer Res. 63, 2284–2291 (2003).
  CAS PubMed Google Scholar
• Wang, H. B. et al. Phospholipase C γ/diacylglycerol-dependent activation of β2-chimaerin restricts EGF-induced Rac signaling. EMBO J. 25, 2062–2074 (2006). This paper provides the first evidence that a Rac-GAP can be regulated by a tyrosine-kinase receptor through a DAG-dependent mechanism. Activation of β2-chimaerin attenuates EGF-induced Rac signalling.
  CAS PubMed PubMed Central Google Scholar
• Siliceo, M. et al. β2-chimaerin provides a diacylglycerol-dependent mechanism for regulation of adhesion and chemotaxis of T cells. J. Cell Sci. 119, 141–152 (2006).
  CAS PubMed Google Scholar
• Buttery, P. et al. The diacylglycerol-binding protein α1-chimaerin regulates dendritic morphology. Proc. Natl Acad. Sci. USA 103, 1924–1929 (2006).
  CAS PubMed PubMed Central Google Scholar
• Yang, C. F., Liu, Y., Leskow, F. C., Weaver, V. M. & Kazanietz, M. G. Rac-GAP-dependent inhibition of breast cancer cell proliferation by β2-chimerin. J. Biol. Chem. 280, 24363–24370 (2005).
  CAS PubMed Google Scholar
• Hoelzinger, D. B. et al. Gene expression profile of glioblastoma multiforme invasive phenotype points to new therapeutic targets. Neoplasia 7, 7–16 (2005).
  CAS PubMed PubMed Central Google Scholar
• Yuan, S. X., Miller, D. W., Barnett, G. H., Hahn, J. F. & Williams, B. R. G. Identification and characterization of human β2-chimaerin- association with malignant transformation in astrocytoma. Cancer Res. 55, 3456–3461 (1995).
  CAS PubMed Google Scholar
• Madani, S., Hichami, A., Charkaoui-Malki, M. & Khan, N. A. Diacylglycerols containing omega 3 and omega 6 fatty acids bind to RasGRP and modulate MAP kinase activation. J. Biol. Chem. 279, 1176–1183 (2004).
  CAS PubMed Google Scholar
• Madani, S., Hichami, A., Legrand, A., Belleville, J. & Khan, N. A. Implication of acyl chain of diacylglycerols in activation of different isoforms of protein kinase C. FASEB J. 15, 2595–2601 (2001).
  CAS PubMed Google Scholar
• Pu, Y. M. et al. A novel diacylglycerol-lactone shows marked selectivity in vitro among C1 domains of protein kinase C (PKC) isoforms α and δ as well as selectivity for RasGRP compared with PKCα. J. Biol. Chem. 280, 27329–27338 (2005).
  CAS PubMed Google Scholar
• Barrett, J. C. Mechanisms of multistep carcinogenesis and carcinogen risk assessment. Environ. Health Perspect. 100, 9–20 (1993).
  CAS PubMed PubMed Central Google Scholar
• Blumberg P. M. et al. Phorbol ester receptors and the in vitro effects of tumor promoters. Ann. N. Y. Acad. Sci. 407, 303–315 (1983).
  CAS PubMed Google Scholar
• Giorgione, J. R., Lin, J. H., McCammon, J. A. & Newton, A. C. Increased membrane affinity of the C1 domain of protein kinase Cδ compensates for the lack of involvement of its C2 domain in membrane recruitment. J. Biol. Chem. 281, 1660–1669 (2006).
  CAS PubMed Google Scholar
• Gallegos, L. L., Kunkel, M. T. & Newton, A. C. Targeting protein kinase C activity reporter to discrete intracellular regions reveals spatiotemporal differences in agonist-dependent signaling. J. Biol. Chem. 281, 30947–30956 (2006).
  CAS PubMed Google Scholar
• Schultz, A., Ling, M. & Larsson, C. Identification of an amino acid residue in the protein kinase CC1b domain crucial for its localization to the Golgi network. J. Biol. Chem. 279, 31750–31760 (2004).
  CAS PubMed Google Scholar
• Prevostel, C., Alice, V., Joubert, D. & Parker, P. J. Protein kinase Cα actively downregulates through caveolae-dependent traffic to an endosomal compartment. J. Cell Sci. 113, 2575–2584 (2000).
  CAS PubMed Google Scholar
• Srivastava, J., Procyk, K. J., Iturrioz, X. & Parker, P. J. Phosphorylation is required for PMA- and cell-cycle-induced degradation of protein kinase Cδ. Biochem. J. 368, 349–355 (2002).
  CAS PubMed PubMed Central Google Scholar
• Lee, H. W., Smith, L., Pettit, G. R., Vinitsky, A. & Smith, J. B. Ubiquitination of protein kinase C-α and degradation by the proteasome. J. Biol. Chem. 271, 20973–20976 (1996).
  CAS PubMed Google Scholar
• Leontieva, O. V. & Black, J. D. Identification of two distinct pathways of protein kinase Cα down-regulation in intestinal epithelial cells. J. Biol. Chem. 279, 5788–5801 (2004).
  CAS PubMed Google Scholar
• Lu, Z. M. et al. Activation of protein kinase C triggers its ubiquitination and degradation. Mol. Cell. Biol. 18, 839–845 (1998).
  CAS PubMed PubMed Central Google Scholar
• Cataisson, C., Pearson, A. J., Torgerson, S., Nedospasov, S. A. & Yuspa, S. H. Protein kinase Cα-mediated chemotaxis of neutrophils requires NF-κB activity but is independent of TNFα signaling in mouse skin in vivo. J. Immunol. 174, 1686–1692 (2005).
  CAS PubMed Google Scholar
• Wang, H. Q. & Smart, R. C. Overexpression of protein kinase C-α in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-α expression but not tumor promotion. J. Cell Sci. 112, 3497–3506 (1999).
  CAS PubMed Google Scholar
• Hara, T. et al. Deficiency of protein kinase Cα in mice results in impairment of epidermal hyperplasia and enhancement of tumor formation in two-stage skin carcinogenesis. Cancer Res. 65, 7356–7362 (2005).
  CAS PubMed Google Scholar
• Liu, Y. et al. Protein kinase CβII regulates its own expression in rat intestinal epithelial cells and the colonic epithelium in vivo. J. Biol. Chem. 279, 45556–45563 (2004).
  CAS PubMed Google Scholar
• Chida, K. et al. Disruption of protein kinase Cη results in impairment of wound healing and enhancement of tumor formation in mouse skin carcinogenesis. Cancer Res. 63, 2404–2408 (2003).
  CAS PubMed Google Scholar
• Felli, M. P. et al. PKCθ mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia. Oncogene 24, 992–1000 (2005).
  CAS PubMed Google Scholar
• Varga, A. et al. Tumor grade-dependent alterations in the protein kinase C isoform pattern in urinary bladder carcinomas. Eur. Urol. 46, 462–465 (2004).
  CAS PubMed Google Scholar
• Benzil, D. L., Finkelstein, S. D., Epstein, M. H. & Finch, P. W. Expression pattern of α-protein kinase-C in human astrocytomas indicates a role in malignant progression. Cancer Res. 52, 2951–2956 (1992).
  CAS PubMed Google Scholar
• Mandil, R. et al. Protein kinase Cα and protein kinase Cδ play opposite roles in the proliferation and apoptosis of glioma cells. Cancer Res. 61, 4612–4619 (2001).
  CAS PubMed Google Scholar
• Ainsworth, P. D., Winstanley, J. H. R., Pearson, J. M., Bishop, H. M. & Garrod, D. R. Protein kinase Cα expression in normal breast, ductal carcinoma in situ and invasive ductal carcinoma. Eur. J. Cancer 40, 2269–2273 (2004).
  CAS PubMed Google Scholar
• Kerfoot, C., Huang, W. D. & Rotenberg, S. A. Immunohistochemical analysis of advanced human breast carcinomas reveals downregulation of protein kinase Cα. J. Histochem. Cytochem. 52, 419–422 (2004).
  CAS PubMed Google Scholar
• Weichert, W., Gekeler, V., Denkert, C., Dietel, M. & Hauptmann, S. Protein kinase C isoform expression in ovarian carcinoma correlates with indicators of poor prognosis. Int. J. Oncol. 23, 633–639 (2003).
  CAS PubMed Google Scholar
• Brenner, W. et al. Protein kinase Cη is associated with progression of renal cell carcinoma (RCC). Anticancer Res. 23, 4001–4006 (2003).
  CAS PubMed Google Scholar
• Verstovsek, G., Byrd, A., Frey, M. R., Petrelli, N. J. & Black, J. D. Colonocyte differentiation is associated with increased expression and altered distribution of protein kinase C isozymes. Gastroenterology 115, 75–85 (1998).
  CAS PubMed Google Scholar
• Hidaka, M. et al. Altered expression of protein-kinase-C in adult T-cell leukemia-cells. Int. J. Hematol. 56, 135–141 (1992).
  CAS PubMed Google Scholar
• Doi, S., Goldstein, D., Hug, H. & Weinstein, I. B. Expression of multiple isoforms of protein-kinase-C in normal human colon mucosa and colon tumors and decreased levels of protein-kinase-C-β and protein-kinase-C-η messenger-RNAs in the tumors. Mol. Carcinogen. 11, 197–203 (1994).
  CAS Google Scholar
• Levy, M. F. et al. Decreased levels of protein-kinase-C enzyme-activity and protein-kinase-C messenger-RNA in primary colon tumors. Dis. Colon Rectum 36, 913–921 (1993).
  CAS PubMed Google Scholar
• Pongracz, J., Clark, P., Neoptolemos, J. P. & Lord, J. M. Expression of protein-kinase-C isoenzymes in colorectal-cancer tissue and their differential activation by different bile-acids. Int. J. Cancer 61, 35–39 (1995).
  CAS PubMed Google Scholar
• Cornford, P. et al. Protein kinase C isoenzyme patterns characteristically modulated in early prostate cancer. Am. J. Pathol. 154, 137–144 (1999).
  CAS PubMed PubMed Central Google Scholar
• Gilhooly, E. M. et al. Loss of expression of protein kinase Cβ is a common phenomenon in human malignant melanoma: a result of transformation or differentiation? Melanoma Res. 11, 355–369 (2001).
  CAS PubMed Google Scholar
• Koren, R. et al. Protein kinase C (PKC) isoenzymes immunohistochemistry in lymph node revealing solution-fixed, paraffin-embedded bladder tumors. Appl. Immunohistochem. Mol. Morphol. 8, 166–171 (2000).
  CAS PubMed Google Scholar
• Langzam, L. et al. Patterns of protein kinase C isoenzyme expression in transitional cell carcinoma of bladder. Am. J. Clinical Pathol. 116, 377–385 (2001).
  CAS Google Scholar
• Kuranami, M. et al. Differential expression of protein-kinase-C isoforms in human colorectal cancers. J. Surgical Res. 58, 233–239 (1995).
  CAS Google Scholar
• Wu, E. X. et al. PKCβ: a rational therapeutic target in diffuse large B-cell lymphoma. Blood 100, 202A–202A (2002).
  Google Scholar
• Hans, C. P. et al. Expression of PKC-β or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma. Modern Pathol. 18, 1377–1384 (2005).
  CAS Google Scholar
• D'Costa, A. M. et al. The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas. Oncogene 25, 378–386 (2006).
  CAS PubMed Google Scholar
• Sharif, T. R. & Sharif, M. Overexpression of protein kinase Cε in astroglial brain tumor derived cell lines and primary tumor samples. Int. J. Oncol. 15, 237–243 (1999).
  CAS PubMed Google Scholar
• Knauf, J. A. et al. Isozyme-specific abnormalities of PKC in thyroid cancer: evidence for post-transcriptional changes in PKCε. J. Clin. Endocrinol. Metab. 87, 2150–2159 (2002).
  CAS PubMed Google Scholar
• Beck, J. et al. Multiple gene expression analysis reveals distinct differences between G2 and G3 stage breast cancers, and correlations of PKCη with MDR1, MRP and LRP gene expression. Br. J. Cancer 77, 87–91 (1998).
  CAS PubMed PubMed Central Google Scholar
• Masso-Welch, P. A. et al. Altered expression and localization of PKCη in human breast tumors. Breast Cancer Res. Treat. 68, 211–223 (2001).
  CAS PubMed Google Scholar
• Blay, P. et al. Protein kinase Cθ is highly expressed in gastrointestinal stromal tumors but not in other mesenchymal neoplasias. Clin. Cancer Res. 10, 4089–4095 (2004).
  CAS PubMed Google Scholar