Protein Kinase C and the Development of Squamous Cell Carcinoma

  • Mitchell F. DenningEmail author


An important role for protein kinase C (PKC) signaling in squamous cell carcinoma (SCC) of the skin has been recognized since the early 1980s, when PKC was discovered to be the major receptor for phorbol ester tumor promoters commonly used in mouse skin chemical carcinogenesis studies. Since then, we have gained a tremendous understanding of the unique roles for different PKC isoforms in keratinocyte, KC, proliferation, differentiation, and apoptosis, as well as how PKC regulation and signaling integrate into the etiology of chemically induced SCC skin. In addition, the role of PKC in ultraviolet (UV)-induced cutaneous SCC is becoming appreciated. This is a significant development as human skin cancers are very common and are caused primarily by exposure to UV radiation. This chapter will summarize our current understanding of PKC function and regulation in normal KCs, as well as the etiology of both chemical and UV-induced cutaneous SCCs.


Chemical Carcinogenesis Cutaneous Squamous Cell Carcinoma Human Squamous Cell Carcinoma Cholesterol Sulfate EGFR Ligand 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



I have permission to use all figures in my chapter because they are originals.


  1. Abbas T, White D, Hui L, Yoshida K, Foster DA, Bargonetti J (2004) Inhibition of human p53 basal transcription by down-regulation of protein kinase C δ. J Biol Chem 279:9970–9977PubMedCrossRefGoogle Scholar
  2. Aldaz CM, Conti CJ, Gimenez IB, Slaga TJ, Klein-Szanto AJ (1985) Cutaneous changes during prolonged application of 12-O-tetradecanoylphorbol-13-acetate on mouse skin and residual effects after cessation of treatment. Cancer Res 45:2753–2759PubMedGoogle Scholar
  3. Aragane Y, Kulms D, Metze D, Wilkes G, Poppelmann B, Luger TA et al (1998) Ultraviolet light induces apoptosis via direct activation of CD95 (Fas/APO-1) independently of its ligand CD95L. J Cell Biol 140:171–182PubMedCrossRefGoogle Scholar
  4. Arnott CH, Scott KA, Moore RJ, Robinson SC, Thompson RG, Balkwill FR (2004) Expression of both TNF-α receptor subtypes is essential for optimal skin tumour development. Oncogene 23:1902–1910PubMedCrossRefGoogle Scholar
  5. Ashida M, Bito T, Budiyanto A, Ichihashi M, Ueda M (2003) Involvement of EGF receptor activation in the induction of cyclooxygenase-2 in HaCaT keratinocytes after UVB. Exp Dermatol 12:445–452PubMedCrossRefGoogle Scholar
  6. Astrup EG, Iversen OH (1983) Cell population kinetics in hairless mouse epidermis following a single topical application of 12-O-tetradecanoylphorbol-13-acetate II. Virchows Arch B Cell Pathol Incl Mol Pathol 42:1–18PubMedCrossRefGoogle Scholar
  7. Aziz MH, Manoharan HT, Verma AK (2007) Protein kinase C ε, which sensitizes skin to sun’s UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3. Cancer Res 67:1385–1394PubMedCrossRefGoogle Scholar
  8. Aziz MH, Wheeler DL, Bhamb B, Verma AK (2006) Protein kinase C δ overexpressing transgenic mice are resistant to chemically but not to UV radiation-induced development of squamous cell carcinomas: a possible link to specific cytokines and cyclooxygenase-2. Cancer Res 66:713–722PubMedCrossRefGoogle Scholar
  9. Balasubramanian S, Efimova T, Eckert RL (2002) Green tea polyphenol stimulates a Ras, MEKK1, MEK3, and p38 cascade to increase activator protein 1 factor-dependent involucrin gene expression in normal human keratinocytes. J Biol Chem 277:1828–1836PubMedCrossRefGoogle Scholar
  10. Bharti A, Kraeft SK, Gounder M, Pandey P, Jin S, Yuan ZM et al (1998) Inactivation of DNA-dependent protein kinase by protein kinase Cδ: implications for apoptosis. Mol Cell Biol 18:6719–6728PubMedGoogle Scholar
  11. Blake RA, Garcia-Paramio P, Parker PJ, Courtneidge SA (1999) Src promotes PKC δ degradation. Cell Growth Differ 10:231–241PubMedGoogle Scholar
  12. Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ (1995) Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377:552–557PubMedCrossRefGoogle Scholar
  13. Cabodi S, Calautti E, Talora C, Kuroki T, Stein PL, Dotto GP (2000) A PKC-η/Fyn-dependent pathway leading to keratinocyte growth arrest and differentiation. Mol Cell 6:1121–1129PubMedCrossRefGoogle Scholar
  14. Cataisson C, Joseloff E, Murillas R, Wang A, Atwell C, Torgerson S et al (2003) Activation of cutaneous protein kinase C α induces keratinocyte apoptosis and intraepidermal inflammation by independent signaling pathways. J Immunol 171:2703–2713PubMedGoogle Scholar
  15. Cataisson C, Ohman R, Patel G, Pearson A, Tsien M, Jay S et al (2009) Inducible cutaneous inflammation reveals a protumorigenic role for keratinocyte CXCR2 in skin carcinogenesis. Cancer Res 69:319–328PubMedCrossRefGoogle Scholar
  16. Cataisson C, Pearson AJ, Torgerson S, Nedospasov SA, Yuspa SH (2005) Protein kinase Cα-mediated chemotaxis of neutrophils requires NF-κB activity but is independent of TNFα signaling in mouse skin in vivo. J Immunol 174:1686–1692PubMedGoogle Scholar
  17. Cataisson C, Pearson AJ, Tsien MZ, Mascia F, Gao JL, Pastore S et al (2006) CXCR2 ligands and G-CSF mediate PKCα-induced intraepidermal inflammation. J Clin Invest 116:2757–2766PubMedCrossRefGoogle Scholar
  18. Chan KS, Sano S, Kiguchi K, Anders J, Komazawa N, Takeda J et al (2004) Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Invest 114:720–728PubMedGoogle Scholar
  19. Chaturvedi V, Qin JZ, Denning MF, Choubey D, Diaz MO, Nickoloff BJ (1999) Apoptosis in proliferating, senescent, and immortalized keratinocytes. J Biol Chem 274:23358–23367PubMedCrossRefGoogle Scholar
  20. Chen N, Ma W, Huang C, Dong Z (1999a) Translocation of protein kinase Cε and protein kinase Cδ to membrane is required for ultraviolet B-induced activation of mitogen-activated protein kinases and apoptosis. J Biol Chem 274:15389–15394PubMedCrossRefGoogle Scholar
  21. Chen W, Dong Z, Valcic S, Timmermann BN, Bowden GT (1999b) Inhibition of ultraviolet B–induced c-fos gene expression and p38 mitogen-activated protein kinase activation by (−)-epigallocatechin gallate in a human keratinocyte cell line. Mol Carcinog 24:79–84PubMedCrossRefGoogle Scholar
  22. Cheng C, Tennenbaum T, Dempsey PJ, Coffey RJ, Yuspa SH, Dlugosz AA (1993) Epidermal growth factor receptor ligands regulate keratin 8 expression in keratinocytes, and transforming growth factor α mediates the induction of keratin 8 by the v-rasHa oncogene. Cell Growth Differ 4:317–327PubMedGoogle Scholar
  23. Chida K, Hara T, Hirai T, Konishi C, Nakamura K, Nakao K et al (2003) Disruption of protein kinase Cη results in impairment of wound healing and enhancement of tumor formation in mouse skin carcinogenesis. Cancer Res 63:2404–2408PubMedGoogle Scholar
  24. Chida K, Murakami A, Tagawa T, Ikuta T, Kuroki T (1995) Cholesterol sulfate, a second messenger for the η isoform of protein kinase C, inhibits promotional phase in mouse skin carcinogenesis. Cancer Res 55:4865–4869PubMedGoogle Scholar
  25. D’Costa AM, Denning MF (2005) A caspase-resistant mutant of PKC-δ protects keratinocytes from UV-induced apoptosis. Cell Death Differ 12:224–232PubMedCrossRefGoogle Scholar
  26. D’Costa AM, Robinson JK, Maududi T, Chaturvedi V, Nickoloff BJ, Denning MF (2006) The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas. Oncogene 25:378–386PubMedGoogle Scholar
  27. Denning MF (2004) Epidermal keratinocytes: regulation of multiple cell phenotypes by multiple protein kinase C isoforms. Int J Biochem Cell Biol 36:1141–1146PubMedCrossRefGoogle Scholar
  28. Denning MF, Dlugosz AA, Howett MK, Yuspa SH (1993) Expression of an oncogenic rasHa gene in murine keratinocytes induces tyrosine phosphorylation and reduced activity of protein kinase C δ. J Biol Chem 268:26079–26081PubMedGoogle Scholar
  29. Denning MF, Dlugosz AA, Williams EK, Szallasi Z, Blumberg PM, Yuspa SH (1995a) Specific protein kinase C isozymes mediate the induction of keratinocyte differentiation markers by calcium. Cell Growth Differ 6:149–157PubMedGoogle Scholar
  30. Denning MF, Kazanietz MG, Blumberg PM, Yuspa SH (1995b) Cholesterol sulfate activates multiple protein kinase C isoenzymes and induces granular cell differentiation in cultured murine keratinocytes. Cell Growth Differ 6:1619–1626PubMedGoogle Scholar
  31. Denning MF, Dlugosz AA, Threadgill DW, Magnuson T, Yuspa SH (1996) Activation of the epidermal growth factor receptor signal transduction pathway stimulates tyrosine phosphorylation of protein kinase C δ. J Biol Chem 271:5325–5331PubMedCrossRefGoogle Scholar
  32. Denning MF, Wang Y, Nickoloff BJ, Wrone-Smith T (1998) Protein kinase Cδ is activated by caspase-dependent proteolysis during ultraviolet radiation-induced apoptosis of human keratinocytes. J Biol Chem 273:29995–30002PubMedCrossRefGoogle Scholar
  33. Denning MF, Dlugosz AA, Cheng C, Dempsey PJ, Coffey RJ, Threadgill DW et al (2000) Cross-talk between epidermal growth factor receptor and protein kinase C during calcium-induced differentiation of keratinocytes. Exp Dermatol 9:192–199PubMedCrossRefGoogle Scholar
  34. Denning MF, Wang Y, Tibudan S, Nickoloff BJ, Qin JZ (2002) Caspase activation and disruption of mitochondrial membrane potential during UV radiation-induced apoptosis of human keratinocyte requires activation of protein kinase C. Cell Death Differ 9:40–52PubMedCrossRefGoogle Scholar
  35. Deucher A, Efimova T, Eckert RL (2002) Calcium-dependent involucrin expression is inversely regulated by protein kinase C (PKC)α and PKCδ. J Biol Chem 277:17032–17040PubMedCrossRefGoogle Scholar
  36. DeVries TA, Neville MC, Reyland ME (2002) Nuclear import of PKCδ is required for apoptosis: identification of a novel nuclear import sequence. EMBO J 21:6050–6060PubMedCrossRefGoogle Scholar
  37. DeVries-Seimon TA, Ohm AM, Humphries MJ, Reyland ME (2007) Induction of apoptosis is driven by nuclear retention of protein kinase C δ. J Biol Chem 282:22307–22314PubMedCrossRefGoogle Scholar
  38. Dlugosz AA, Cheng C, Williams EK, Dharia AG, Denning MF, Yuspa SH (1994) Alterations in murine keratinocyte differentiation induced by activated rasHa genes are mediated by protein kinase C-α. Cancer Res 54:6413–6420PubMedGoogle Scholar
  39. Dlugosz AA, Mischak H, Mushinski JF, Yuspa SH (1992) Transcripts encoding protein kinase C-α, -δ, -ε, - ζ, and -η are expressed in basal and differentiating mouse keratinocytes in vitro and exhibit quantitative changes in neoplastic cells. Mol Carcinog 5:286–292PubMedCrossRefGoogle Scholar
  40. Dlugosz AA, Yuspa SH (1993) Coordinate changes in gene expression which mark the spinous to granular cell transition in epidermis are regulated by protein kinase C. J Cell Biol 120:217–225PubMedCrossRefGoogle Scholar
  41. Dlugosz AA, Yuspa SH (1991) Staurosporine induces protein kinase C agonist effects and maturation of normal and neoplastic mouse keratinocytes in vitro. Cancer Res 51:4677–4684PubMedGoogle Scholar
  42. Efimova T, Eckert RL (2000) Regulation of human involucrin promoter activity by novel protein kinase C isoforms. J Biol Chem 275:1601–1607PubMedCrossRefGoogle Scholar
  43. Efimova T, Deucher A, Kuroki T, Ohba M, Eckert RL (2002) Novel protein kinase C isoforms regulate human keratinocyte differentiation by activating a p38δ mitogen-activated protein kinase cascade that targets CCAAT/enhancer-binding protein α. J Biol Chem 277:31753–31760PubMedCrossRefGoogle Scholar
  44. Efimova T, Broome AM, Eckert RL (2004) Protein kinase Cδ regulates keratinocyte death and survival by regulating activity and subcellular localization of a p38δ-extracellular signal-regulated kinase 1/2 complex. Mol Cell Biol 24:8167–8183PubMedCrossRefGoogle Scholar
  45. Einspahr JG, Bowden GT, Alberts DS, McKenzie N, Saboda K, Warneke J et al (2008) Cross-validation of murine UV signal transduction pathways in human skin. Photochem Photobiol 84:463–476PubMedCrossRefGoogle Scholar
  46. Geiges D, Marks F, Gschwendt M (1995) Loss of protein kinase C delta from human HaCaT keratinocytes upon ras transfection is mediated by TGF alpha. Exp Cell Res 219:299–303PubMedCrossRefGoogle Scholar
  47. Gilmour SK, Verma AK, Madara T, O’Brien TG (1987) Regulation of ornithine decarboxylase gene expression in mouse epidermis and epidermal tumors during two-stage tumorigenesis. Cancer Res 47:1221–1225PubMedGoogle Scholar
  48. Gonzalez-Guerrico AM, Kazanietz MG (2005) Phorbol ester-induced apoptosis in prostate cancer cells via autocrine activation of the extrinsic apoptotic cascade: A key role for protein kinase Cδ. J Biol Chem 280:38982–38991PubMedCrossRefGoogle Scholar
  49. Hansen LA, Monteiro-Riviere NA, Smart RC (1990) Differential down-regulation of epidermal protein kinase C by 12-O-tetradecanoylphorbol-13-acetate and diacylglycerol: association with epidermal hyperplasia and tumor promotion. Cancer Res 50:5740–5745PubMedGoogle Scholar
  50. Hara T, Saito Y, Hirai T, Nakamura K, Nakao K, Katsuki M et al (2005) 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 65:7356–7362PubMedCrossRefGoogle Scholar
  51. Hennings H, Michael D, Lichti U, Yuspa SH (1987) Response of carcinogen-altered mouse epidermal cells to phorbol ester tumor promoters and calcium. J Invest Dermatol 88:60–65PubMedCrossRefGoogle Scholar
  52. Hu Y, Baud V, Oga T, Kim KI, Yoshida K, Karin M (2001) IKKα controls formation of the epidermis independently of NF-κB. Nature 410:710–714PubMedCrossRefGoogle Scholar
  53. Huang RP, Wu JX, Fan Y, Adamson ED (1996) UV activates growth factor receptors via reactive oxygen intermediates. J Cell Biol 133:211–220PubMedCrossRefGoogle Scholar
  54. Huitfeldt HS, Heyden A, Clausen OP, Thrane EV, Roop D, Yuspa SH (1991) Altered regulation of growth and expression of differentiation-associated keratins in benign mouse skin tumors. Carcinogenesis 12:2063–2067PubMedCrossRefGoogle Scholar
  55. Humphries MJ, Limesand KH, Schneider JC, Nakayama KI, Anderson SM, Reyland ME (2006) Suppression of apoptosis in the protein kinase C δ null mouse in vivo. J Biol Chem 281:9728–9737PubMedCrossRefGoogle Scholar
  56. Huppi K, Siwarski D, Goodnight J, Mischak H (1994) Assignment of the protein kinase C delta polypeptide gene (PRKCD) to human chromosome 3 and mouse chromosome 14. Genomics 19:161–162PubMedCrossRefGoogle Scholar
  57. Ikuta T, Chida K, Tajima O, Matsuura Y, Iwamori M, Ueda Y et al (1994) Cholesterol sulfate, a novel activator for the eta isoform of protein kinase C. Cell Growth Differ 5:943–947PubMedGoogle Scholar
  58. Ishino K, Ohba M, Kashiwagi M, Kawabe S, Chida K, Kuroki T (1998) Phorbol ester-induced G1 arrest in BALB/MK-2 mouse keratinocytes is mediated by δ and η isoforms of protein kinase C. Jpn J Cancer Res 89:1126–1133PubMedGoogle Scholar
  59. Jansen AP, Dreckschmidt NE, Verwiebe EG, Wheeler DL, Oberley TD, Verma AK (2001a) Relation of the induction of epidermal ornithine decarboxylase and hyperplasia to the different skin tumor-promotion susceptibilities of protein kinase C alpha, -delta and -epsilon transgenic mice. Int J Cancer 93:635–643PubMedCrossRefGoogle Scholar
  60. Jansen AP, Verwiebe EG, Dreckschmidt NE, Wheeler DL, Oberley TD, Verma AK (2001b) Protein kinase C-epsilon transgenic mice: a unique model for metastatic squamous cell carcinoma. Cancer Res 61:808–812PubMedGoogle Scholar
  61. Jerome-Morais A, Rahn HR, Tibudan SS, Denning MF (2009) Role for Protein Kinase C-α in Keratinocyte Growth Arrest. J Invest Dermatol. doi:10.1038/jid.2009.74Google Scholar
  62. Joseloff E, Cataisson C, Aamodt H, Ocheni H, Blumberg P, Kraker AJ et al (2002) Src family kinases phosphorylate protein kinase C δ on tyrosine residues and modify the neoplastic phenotype of skin keratinocytes. J Biol Chem 277:12318–12323PubMedCrossRefGoogle Scholar
  63. Kashiwagi M, Ohba M, Watanabe H, Ishino K, Kasahara K, Sanai Y et al (2000) PKCη associates with cyclin E/cdk2/p21 complex, phosphorylates p21 and inhibits cdk2 kinase in keratinocytes. Oncogene 19:6334–6341PubMedCrossRefGoogle Scholar
  64. Kashiwagi M, Ohba M, Chida K, Kuroki T (2002) Protein kinase C eta (PKCη): its involvement in keratinocyte differentiation. J Biochem (Tokyo) 132:853–857Google Scholar
  65. Kennard MD, Kang DC, Montgomery RL, Butler AP (1995) Expression of epidermal ornithine decarboxylase and nuclear proto-oncogenes in phorbol ester tumor promotion-sensitive and -resistant mice. Mol Carcinog 12:14–22PubMedCrossRefGoogle Scholar
  66. Kischel T, Harbers M, Stabel S, Borowski P, Muller K, Hilz H (1989) Tumor promotion and depletion of protein kinase C in epidermal JB6 cells. Biochem Biophys Res Commun 165:981–987PubMedCrossRefGoogle Scholar
  67. Koizumi H, Kohno Y, Osada S, Ohno S, Ohkawara A, Kuroki T (1993) Differentiation-associated localization of nPKC η, a Ca2+-independent protein kinase C, in normal human skin and skin diseases. J Invest Dermatol 101:858–863PubMedCrossRefGoogle Scholar
  68. Lee E, Yuspa SH (1991) Changes in inositol phosphate metabolism are associated with terminal differentiation and neoplasia in mouse keratinocytes. Carcinogenesis 12:1651–1658PubMedCrossRefGoogle Scholar
  69. Lee E, Punnonen K, Cheng C, Glick A, Dlugosz A, Yuspa SH (1992) Analysis of phospholipid metabolism in murine keratinocytes transformed by the v-ras oncogene: relationship of phosphatidylinositol turnover and cytokine stimulation to the transformed phenotype. Carcinogenesis 13:2367–2373PubMedCrossRefGoogle Scholar
  70. Lee SJ, Kim DC, Choi BH, Ha H, Kim KT (2006) Regulation of p53 by activated protein kinase C-δ during nitric oxide-induced dopaminergic cell death. J Biol Chem 281:2215–2224PubMedCrossRefGoogle Scholar
  71. Leitges M, Mayr M, Braun U, Mayr U, Li C, Pfister G et al (2001a) Exacerbated vein graft arteriosclerosis in protein kinase Cδ-null mice. J Clin Invest 108:1505–1512PubMedGoogle Scholar
  72. Leitges M, Sanz L, Martin P, Duran A, Braun U, Garcia JF et al (2001b) Targeted disruption of the zetaPKC gene results in the impairment of the NF-κB pathway. Mol Cell 8:771–780PubMedCrossRefGoogle Scholar
  73. Lenz JC, Reusch HP, Albrecht N, Schultz G, Schaefer M (2002) Ca2+-controlled competitive diacylglycerol binding of protein kinase C isoenzymes in living cells. J Cell Biol 159:291–302PubMedCrossRefGoogle Scholar
  74. Lessmann E, Leitges M, Huber M (2006) A redundant role for PKC-ε in mast cell signaling and effector function. Int Immunol 18:767–773PubMedCrossRefGoogle Scholar
  75. Li L, Tucker RW, Hennings H, Yuspa SH (1995a) Chelation of intracellular Ca2+ inhibits murine keratinocyte differentiation in vitro. J Cell Physiol 163:105–114PubMedCrossRefGoogle Scholar
  76. Li L, Tucker RW, Hennings H, Yuspa SH (1995b) Inhibitors of the intracellular Ca2+-ATPase in cultured mouse keratinocytes reveal components of terminal differentiation that are regulated by distinct intracellular Ca2+ compartments. Cell Growth Differ 6:1171–1184PubMedGoogle Scholar
  77. Li L, Lorenzo PS, Bogi K, Blumberg PM, Yuspa SH (1999) 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 19:8547–8558PubMedGoogle Scholar
  78. Li Y, Wheeler DL, Alters W, Chaiswing L, Verma AK, Oberley TD (2005) Early epidermal destruction with subsequent epidermal hyperplasia is a unique feature of the papilloma-independent squamous cell carcinoma phenotype in PKCepsilon overexpressing transgenic mice. Toxicol Pathol 33:684–694PubMedCrossRefGoogle Scholar
  79. Liu J, Chen J, Dai Q, Lee RM (2003) Phospholipid scramblase 3 is the mitochondrial target of protein kinase C δ-induced apoptosis. Cancer Res 63:1153–1156PubMedGoogle Scholar
  80. Liu H, Lu ZG, Miki Y, Yoshida K (2007) Protein kinase C δ induces transcription of the TP53 tumor suppressor gene by controlling death-promoting factor Btf in the apoptotic response to DNA damage. Mol Cell Biol 27:8480–8491PubMedCrossRefGoogle Scholar
  81. Matsui MS, Wang N, DeLeo VA (1996) Ultraviolet radiation B induces differentiation and protein kinase C in normal human epidermal keratinocytes. Photodermatol Photoimmunol Photomed 12:103–108PubMedGoogle Scholar
  82. Matsumura M, Tanaka N, Kuroki T, Ichihashi M, Ohba M (2003) The eta isoform of protein kinase C inhibits UV-induced activation of caspase-3 in normal human keratinocytes. Biochem Biophys Res Commun 303:350–356PubMedCrossRefGoogle Scholar
  83. Mills KJ, Bocckino SB, Burns DJ, Loomis CR, Smart RC (1992) Alterations in protein kinase C isozymes α and β2 in activated Ha-ras containing papillomas in the absence of an increase in diacylglycerol. Carcinogenesis 13:1113–1120PubMedCrossRefGoogle Scholar
  84. Miyamoto A, Nakayama K, Imaki H, Hirose S, Jiang Y, Abe M et al (2002) Increased proliferation of B cells and auto-immunity in mice lacking protein kinase C δ. Nature 416:865–869PubMedCrossRefGoogle Scholar
  85. Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N et al (1999) Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis. Nat Med 5:828–831PubMedCrossRefGoogle Scholar
  86. Nijhawan D, Fang M, Traer E, Zhong Q, Gao W, Du F et al (2003) Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev 17:1475–1486PubMedCrossRefGoogle Scholar
  87. Niwa K, Inanami O, Yamamori T, Ohta T, Hamasu T, Karino T et al (2002) Roles of protein kinase C δ in the accumulation of P53 and the induction of apoptosis in H2O2-treated bovine endothelial cells. Free Radic Res 36:1147–1153PubMedCrossRefGoogle Scholar
  88. Ohba M, Ishino K, Kashiwagi M, Kawabe S, Chida K, Huh NH et al (1998) Induction of differentiation in normal human keratinocytes by adenovirus-mediated introduction of the eta and delta isoforms of protein kinase C. Mol Cell Biol 18:5199–5207PubMedGoogle Scholar
  89. Pan Q, Bao LW, Teknos TN, Merajver SD (2006) 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 66:9379–9384PubMedCrossRefGoogle Scholar
  90. Pierceall WE, Goldberg LH, Tainsky MA, Mukhopadhyay T, Ananthaswamy HN (1991) Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog 4:196–202PubMedCrossRefGoogle Scholar
  91. Prowse DM, Lee D, Weiner L, Jiang N, Magro CM, Baden HP et al (1999) Ectopic expression of the nude gene induces hyperproliferation and defects in differentiation: implications for the self-renewal of cutaneous epithelia. Dev Biol 212:54–67PubMedCrossRefGoogle Scholar
  92. Punnonen K, Yuspa SH (1992) Ultraviolet light irradiation increases cellular diacylglycerol and induces translocation of diacylglycerol kinase in murine keratinocytes. J Invest Dermatol 99:221–226PubMedCrossRefGoogle Scholar
  93. Quintanilla M, Brown K, Ramsden M, Balmain A (1986) Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322:78–80PubMedCrossRefGoogle Scholar
  94. Reddig PJ, Dreckschimdt NE, Ahrens H, Simsiman R, Tseng CP, Zou J et al (1999) Transgenic mice overexpressing protein kinase C δ in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 59:5710–5718PubMedGoogle Scholar
  95. Reddig PJ, Dreckschmidt NE, Zou J, Bourguignon SE, Oberley TD, Verma AK (2000) Transgenic mice overexpressing protein kinase C ε in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion. Cancer Res 60:595–602PubMedGoogle Scholar
  96. Roop DR, Lowy DR, Tambourin PE, Strickland J, Harper JR, Balaschak M et al (1986) An activated Harvey ras oncogene produces benign tumours on mouse epidermal tissue. Nature 323:822–824PubMedCrossRefGoogle Scholar
  97. Rosette C, Karin M (1996) Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors. Science 274:1194–1197PubMedCrossRefGoogle Scholar
  98. Rutberg SE, Saez E, Glick A, Dlugosz AA, Spiegelman BM, Yuspa SH (1996) Differentiation of mouse keratinocytes is accompanied by PKC-dependent changes in AP-1 proteins. Oncogene 13:167–176PubMedGoogle Scholar
  99. Ryer EJ, Sakakibara K, Wang C, Sarkar D, Fisher PB, Faries PL et al (2005) Protein kinase C delta induces apoptosis of vascular smooth muscle cells through induction of the tumor suppressor p53 by both p38-dependent and p38-independent mechanisms. J Biol Chem 280:35310–35317PubMedCrossRefGoogle Scholar
  100. Sakaguchi M, Miyazaki M, Sonegawa H, Kashiwagi M, Ohba M, Kuroki T et al (2004) PKCα mediates TGFβ-induced growth inhibition of human keratinocytes via phosphorylation of S100/A11. J Cell Biol 164:979–984PubMedCrossRefGoogle Scholar
  101. Sakaguchi M, Sonegawa H, Nukui T, Sakaguchi Y, Miyazaki M, Namba M et al (2005) Bifurcated converging pathways for high Ca2 + - and TGFbeta-induced inhibition of growth of normal human keratinocytes. Proc Natl Acad Sci USA 102:13921–13926PubMedCrossRefGoogle Scholar
  102. Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K et al (2005a) Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med 11:43–49PubMedCrossRefGoogle Scholar
  103. Sano S, Chan KS, Kira M, Kataoka K, Takagi S, Tarutani M et al (2005b) Signal transducer and activator of transcription 3 is a key regulator of keratinocyte survival and proliferation following UV irradiation. Cancer Res 65:5720–5729PubMedCrossRefGoogle Scholar
  104. Schonwasser DC, Marais RM, Marshall CJ, Parker PJ (1998) Activation of the mitogen-activated protein kinase/extracellular signal- regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol Cell Biol 18:790–798PubMedGoogle Scholar
  105. Seitz CS, Lin Q, Deng H, Khavari PA (1998) Alterations in NF-κB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-κB. Proc Natl Acad Sci USA 95:2307–2312PubMedCrossRefGoogle Scholar
  106. Seitz CS, Deng H, Hinata K, Lin Q, Khavari PA (2000) Nuclear factor kappaB subunits induce epithelial cell growth arrest. Cancer Res 60:4085–4092PubMedGoogle Scholar
  107. Seo HR, Kwan YW, Cho CK, Bae S, Lee SJ, Soh JW et al (2004) PKCα induces differentiation through ERK1/2 phosphorylation in mouse keratinocytes. Exp Mol Med 36:292–299PubMedGoogle Scholar
  108. Sheikh MS, Antinore MJ, Huang Y, Fornace AJ Jr (1998) Ultraviolet-irradiation-induced apoptosis is mediated via ligand independent activation of tumor necrosis factor receptor 1. Oncogene 17:2555–2563PubMedCrossRefGoogle Scholar
  109. Sitailo LA, Tibudan SS, Denning MF (2004) Bax activation and induction of apoptosis in human keratinocytes by the protein kinase C δ catalytic domain. J Invest Dermatol 123:434–443PubMedCrossRefGoogle Scholar
  110. Sitailo LA, Tibudan SS, Denning MF (2006) The protein kinase Cδ catalytic fragment targets Mcl-1 for degradation to trigger apoptosis. J Biol Chem 281(40):29703–29710PubMedCrossRefGoogle Scholar
  111. Skouv J, Christensen B, Autrup H (1987) Differential induction of transcription of c-myc and c-fos proto-oncogenes by 12-O-tetradecanoylphorbol-13-acetate in mortal and immortal human urothelial cells. J Cell Biochem 34:71–79PubMedCrossRefGoogle Scholar
  112. Soehnge H, Ouhtit A, Ananthaswamy ON (1997) Mechanisms of induction of skin cancer by UV radiation. Front Biosci 2:d538–d551PubMedGoogle Scholar
  113. Spencer JM, Kahn SM, Jiang W, DeLeo VA, Weinstein IB (1995) Activated ras genes occur in human actinic keratoses, premalignant precursors to squamous cell carcinomas. Arch Dermatol 131:796–800PubMedCrossRefGoogle Scholar
  114. Szallasi Z, Denning MF, Chang EY, Rivera J, Yuspa SH, Lehel C et al (1995) Development of a rapid approach to identification of tyrosine phosphorylation sites: application to PKC δ phosphorylated upon activation of the high affinity receptor for IgE in rat basophilic leukemia cells. Biochem Biophys Res Commun 214:888–894PubMedCrossRefGoogle Scholar
  115. Takahashi H, Asano K, Manabe A, Kinouchi M, Ishida-Yamamoto A, Iizuka H (1998) The α and η isoforms of prtoein kinase C stimulate transcription of human involucrin gene. J Invest Dermatol 110:218–223PubMedCrossRefGoogle Scholar
  116. Takeda K, Takeuchi O, Tsujimura T, Itami S, Adachi O, Kawai T et al (1999) Limb and skin abnormalities in mice lacking IKKα. Science 284:313–316PubMedCrossRefGoogle Scholar
  117. Tennenbaum T, Weiner AK, Belanger AJ, Glick AB, Hennings H, Yuspa SH (1993) The suprabasal expression of alpha 6 beta 4 integrin is associated with a high risk for malignant progression in mouse skin carcinogenesis. Cancer Res 53:4803–4810PubMedGoogle Scholar
  118. Tibudan SS, Wang Y, Denning MF (2002) Activation of protein kinase C triggers irreversible cell cycle withdrawal in human keratinocytes. J Invest Dermatol 119:1282–1289PubMedCrossRefGoogle Scholar
  119. Tu CL, Chang W, Bikle DD (2001) The extracellular calcium-sensing receptor is required for calcium-induced differentiation in human keratinocytes. J Biol Chem 276:41079–41085PubMedCrossRefGoogle Scholar
  120. Tu CL, Chang W, Xie Z, Bikle DD (2008) Inactivation of the calcium sensing receptor inhibits E-cadherin-mediated cell-cell adhesion and calcium-induced differentiation in human epidermal keratinocytes. J Biol Chem 283:3519–3528PubMedCrossRefGoogle Scholar
  121. Ueda E, Ohno S, Kuroki T, Livneh E, Yamada K, Yamanishi K et al (1996a) The eta isoform of protein kinase C mediates transcriptional activation of the human transglutaminase 1 gene. J Biol Chem 271:9790–9794PubMedCrossRefGoogle Scholar
  122. Ueda Y, Hirai S, Osada S, Suzuki A, Mizuno K, Ohno S (1996b) Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf. J Biol Chem 271:23512–23519PubMedCrossRefGoogle Scholar
  123. Urtreger AJ, Grossoni VC, Falbo KB, Kazanietz MG, de Kier B, Joffe ED (2005) Atypical protein kinase C-ζ modulates clonogenicity, motility, and secretion of proteolytic enzymes in murine mammary cells. Mol Carcinog 42:29–39PubMedCrossRefGoogle Scholar
  124. Verma AK, Wheeler DL, Ness KJ, Martin KE (2005) Protein kinase C δ is not a tumor suppressor in ultraviolet light-induced mouse skin carcinogenesis. Proc Am Assoc Cancer Res 46:3926Google Scholar
  125. Verma AK, Wheeler DL, Aziz MH, Manoharan H (2006) Protein kinase Cε and development of squamous cell carcinoma, the nonmelanoma human skin cancer. Mol Carcinog 45:381–388PubMedCrossRefGoogle Scholar
  126. Vitasa BC, Taylor HR, Strickland PT, Rosenthal FS, West S, Abbey H et al (1990) Association of nonmelanoma skin cancer and actinic keratosis with cumulative solar ultraviolet exposure in Maryland watermen. Cancer 65:2811–2817PubMedCrossRefGoogle Scholar
  127. Wang HQ, Smart RC (1999) 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-alpha expression but not tumor promotion. J Cell Sci 112:3497–3506PubMedGoogle Scholar
  128. Wang HQ, Kim MP, Tiano HF, Langenbach R, Smart RC (2001) Protein kinase C-alpha coordinately regulates cytosolic phospholipase A(2) activity and the expression of cyclooxygenase-2 through different mechanisms in mouse keratinocytes. Mol Pharmacol 59:860–866PubMedGoogle Scholar
  129. Wheeler DL, Reddig PJ, Dreckschmidt NE, Leitges M, Verma AK (2002) Protein kinase C δ-mediated signal to ornithine decarboxylase induction is independent of skin tumor suppression. Oncogene 21:3620–3630PubMedCrossRefGoogle Scholar
  130. Wheeler DL, Ness KJ, Oberley TD, Verma AK (2003) Protein kinase C ε is linked to 12-O-tetradecanoylphorbol-13-acetate-induced tumor necrosis factor-alpha ectodomain shedding and the development of metastatic squamous cell carcinoma in protein kinase C epsilon transgenic mice. Cancer Res 63:6547–6555PubMedGoogle Scholar
  131. Wheeler DL, Martin KE, Ness KJ, Li Y, Dreckschmidt NE, Wartman M et al (2004) Protein kinase C ε is an endogenous photosensitizer that enhances ultraviolet radiation-induced cutaneous damage and development of squamous cell carcinomas. Cancer Res 64:7756–7765PubMedCrossRefGoogle Scholar
  132. Wheeler DL, Li Y, Verma AK (2005) Protein kinase C ε signals ultraviolet light-induced cutaneous damage and development of squamous cell carcinoma possibly through Induction of specific cytokines in a paracrine mechanism. Photochem Photobiol 81:9–18PubMedCrossRefGoogle Scholar
  133. Worden B, Yang XP, Lee TL, Bagain L, Yeh NT, Cohen JG et al (2005) Hepatocyte growth factor/scatter factor differentially regulates expression of proangiogenic factors through Egr-1 in head and neck squamous cell carcinoma. Cancer Res 65:7071–7080PubMedCrossRefGoogle Scholar
  134. Xie Z, Bikle DD (2007) The recruitment of phosphatidylinositol 3-kinase to the E-cadherin-catenin complex at the plasma membrane is required for calcium-induced phospholipase C-gamma1 activation and human keratinocyte differentiation. J Biol Chem 282:8695–8703PubMedCrossRefGoogle Scholar
  135. Xie Z, Chang SM, Pennypacker SD, Liao EY, Bikle DD (2009) Phosphatidylinositol-4-phosphate 5-kinase 1 alpha mediates extracellular calcium-induced keratinocyte differentiation. Mol Biol Cell 20:1695–1704PubMedCrossRefGoogle Scholar
  136. Yamaguchi T, Miki Y, Yoshida K (2007) Protein kinase C δ activates IκB-kinase α to induce the p53 tumor suppressor in response to oxidative stress. Cell Signal 19:2088–2097PubMedCrossRefGoogle Scholar
  137. Yang LC, Ng DC, Bikle DD (2003) Role of protein kinase C α in calcium induced keratinocyte differentiation: defective regulation in squamous cell carcinoma. J Cell Physiol 195:249–259PubMedCrossRefGoogle Scholar
  138. Yoshida K (2007) PKCδ signaling: Mechanisms of DNA damage response and apoptosis. Cell Signal 19:892–901PubMedCrossRefGoogle Scholar
  139. Yoshida K, Liu H, Miki Y (2006) Protein kinase C δ regulates Ser46 phosphorylation of p53 tumor suppressor in the apoptotic response to DNA damage. J Biol Chem 281:5734–5740PubMedCrossRefGoogle Scholar
  140. Youmell M, Park SJ, Basu S, Price BD (1998) Regulation of the p53 protein by protein kinase Cα and protein kinase Cζ. Biochem Biophys Res Commun 245:514–518PubMedCrossRefGoogle Scholar
  141. Yuspa SH, Lichti U, Ben T, Patterson E, Hennings H, Slaga TJ et al (1976) Phorbol esters stimulate DNA synthesis and ornithine decarboxylase activity in mouse epidermal cell cultures. Nature 262:402–404PubMedCrossRefGoogle Scholar
  142. Yuspa SH, Kilkenny AE, Stanley J, Lichti U (1985) Keratinocytes blocked in phorbol ester-responsive early stage of terminal differentiation by sarcoma viruses. Nature 314:459–462PubMedCrossRefGoogle Scholar
  143. Zang Q, Lu Z, Curto M, Barile N, Shalloway D, Foster DA (1997) Association between v-Src and protein kinase C δ in v-Src- transformed fibroblasts. J Biol Chem 272:13275–13280PubMedCrossRefGoogle Scholar
  144. Zhang W, Hanks AN, Boucher K, Florell SR, Allen SM, Alexander A et al (2005) UVB-induced apoptosis drives clonal expansion during skin tumor development. Carcinogenesis 26:249–257PubMedCrossRefGoogle Scholar
  145. Zhu L, Brodie C, Balasubramanian S, Eckert RL (2008) Multiple PKCδ tyrosine residues are required for PKCδ-dependent activation of involucrin expression – a key role of PKCδ-Y311. J Invest Dermatol 128:833–845PubMedCrossRefGoogle Scholar
  146. Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J et al (1994) Sunburn and p53 in the onset of skin cancer. Nature 372:773–776PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of PathologyCardinal Bernardin Cancer Center, Loyola University Medical CenterMaywoodUSA

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