Skip to main content
SpringerLink
Log in

Protein Kinase C and the Development of Squamous Cell Carcinoma

  • Chapter
  • First Online:
Signaling Pathways in Squamous Cancer

  • 568 Accesses

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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 279:9970–9977

    Article  PubMed  CAS  Google Scholar 

  • 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 45:2753–2759

    PubMed  CAS  Google Scholar 

  • 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 140:171–182

    Article  PubMed  CAS  Google Scholar 

  • 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 23:1902–1910

    Article  PubMed  CAS  Google Scholar 

  • 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 12:445–452

    Article  PubMed  CAS  Google Scholar 

  • 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 42:1–18

    Article  PubMed  CAS  Google Scholar 

  • 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 67:1385–1394

    Article  PubMed  CAS  Google Scholar 

  • 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 66:713–722

    Article  PubMed  CAS  Google Scholar 

  • 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 277:1828–1836

    Article  PubMed  CAS  Google Scholar 

  • 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 18:6719–6728

    PubMed  CAS  Google Scholar 

  • Blake RA, Garcia-Paramio P, Parker PJ, Courtneidge SA (1999) Src promotes PKC δ degradation. Cell Growth Differ 10:231–241

    PubMed  CAS  Google Scholar 

  • Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ (1995) Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377:552–557

    Article  PubMed  CAS  Google Scholar 

  • 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 6:1121–1129

    Article  PubMed  CAS  Google Scholar 

  • 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 171:2703–2713

    PubMed  CAS  Google Scholar 

  • 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 69:319–328

    Article  PubMed  CAS  Google Scholar 

  • 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 174:1686–1692

    PubMed  CAS  Google Scholar 

  • 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 116:2757–2766

    Article  PubMed  CAS  Google Scholar 

  • 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 114:720–728

    PubMed  CAS  Google Scholar 

  • Chaturvedi V, Qin JZ, Denning MF, Choubey D, Diaz MO, Nickoloff BJ (1999) Apoptosis in proliferating, senescent, and immortalized keratinocytes. J Biol Chem 274:23358–23367

    Article  PubMed  CAS  Google Scholar 

  • 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 274:15389–15394

    Article  PubMed  CAS  Google Scholar 

  • 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 24:79–84

    Article  PubMed  CAS  Google Scholar 

  • 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 4:317–327

    PubMed  CAS  Google Scholar 

  • 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 63:2404–2408

    PubMed  CAS  Google Scholar 

  • 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 55:4865–4869

    PubMed  CAS  Google Scholar 

  • D’Costa AM, Denning MF (2005) A caspase-resistant mutant of PKC-δ protects keratinocytes from UV-induced apoptosis. Cell Death Differ 12:224–232

    Article  PubMed  CAS  Google Scholar 

  • 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 25:378–386

    PubMed  Google Scholar 

  • Denning MF (2004) Epidermal keratinocytes: regulation of multiple cell phenotypes by multiple protein kinase C isoforms. Int J Biochem Cell Biol 36:1141–1146

    Article  PubMed  CAS  Google Scholar 

  • 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 268:26079–26081

    PubMed  CAS  Google Scholar 

  • 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 6:149–157

    PubMed  CAS  Google Scholar 

  • 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 6:1619–1626

    PubMed  CAS  Google Scholar 

  • 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 271:5325–5331

    Article  PubMed  CAS  Google Scholar 

  • 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 273:29995–30002

    Article  PubMed  CAS  Google Scholar 

  • 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 9:192–199

    Article  PubMed  CAS  Google Scholar 

  • 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 9:40–52

    Article  PubMed  CAS  Google Scholar 

  • 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 277:17032–17040

    Article  PubMed  CAS  Google Scholar 

  • DeVries TA, Neville MC, Reyland ME (2002) Nuclear import of PKCδ is required for apoptosis: identification of a novel nuclear import sequence. EMBO J 21:6050–6060

    Article  PubMed  CAS  Google Scholar 

  • 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 282:22307–22314

    Article  PubMed  CAS  Google Scholar 

  • 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 54:6413–6420

    PubMed  CAS  Google Scholar 

  • 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 5:286–292

    Article  PubMed  CAS  Google Scholar 

  • 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 120:217–225

    Article  PubMed  CAS  Google Scholar 

  • Dlugosz AA, Yuspa SH (1991) Staurosporine induces protein kinase C agonist effects and maturation of normal and neoplastic mouse keratinocytes in vitro. Cancer Res 51:4677–4684

    PubMed  CAS  Google Scholar 

  • Efimova T, Eckert RL (2000) Regulation of human involucrin promoter activity by novel protein kinase C isoforms. J Biol Chem 275:1601–1607

    Article  PubMed  CAS  Google Scholar 

  • 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 277:31753–31760

    Article  PubMed  CAS  Google Scholar 

  • 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 24:8167–8183

    Article  PubMed  CAS  Google Scholar 

  • 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 84:463–476

    Article  PubMed  CAS  Google Scholar 

  • 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 219:299–303

    Article  PubMed  CAS  Google Scholar 

  • 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 47:1221–1225

    PubMed  CAS  Google Scholar 

  • 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 280:38982–38991

    Article  PubMed  CAS  Google Scholar 

  • 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 50:5740–5745

    PubMed  CAS  Google Scholar 

  • 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 65:7356–7362

    Article  PubMed  CAS  Google Scholar 

  • 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 88:60–65

    Article  PubMed  CAS  Google Scholar 

  • Hu Y, Baud V, Oga T, Kim KI, Yoshida K, Karin M (2001) IKKα controls formation of the epidermis independently of NF-κB. Nature 410:710–714

    Article  PubMed  CAS  Google Scholar 

  • Huang RP, Wu JX, Fan Y, Adamson ED (1996) UV activates growth factor receptors via reactive oxygen intermediates. J Cell Biol 133:211–220

    Article  PubMed  CAS  Google Scholar 

  • 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 12:2063–2067

    Article  PubMed  CAS  Google Scholar 

  • 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 281:9728–9737

    Article  PubMed  CAS  Google Scholar 

  • 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 19:161–162

    Article  PubMed  CAS  Google Scholar 

  • 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 5:943–947

    PubMed  CAS  Google Scholar 

  • 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 89:1126–1133

    PubMed  CAS  Google Scholar 

  • 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 93:635–643

    Article  PubMed  CAS  Google Scholar 

  • 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 61:808–812

    PubMed  CAS  Google Scholar 

  • 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.2009.74

    Google Scholar 

  • 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 277:12318–12323

    Article  PubMed  CAS  Google Scholar 

  • 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 19:6334–6341

    Article  PubMed  CAS  Google Scholar 

  • Kashiwagi M, Ohba M, Chida K, Kuroki T (2002) Protein kinase C eta (PKCη): its involvement in keratinocyte differentiation. J Biochem (Tokyo) 132:853–857

    CAS  Google Scholar 

  • 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 12:14–22

    Article  PubMed  CAS  Google Scholar 

  • 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 165:981–987

    Article  PubMed  CAS  Google Scholar 

  • 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 101:858–863

    Article  PubMed  CAS  Google Scholar 

  • Lee E, Yuspa SH (1991) Changes in inositol phosphate metabolism are associated with terminal differentiation and neoplasia in mouse keratinocytes. Carcinogenesis 12:1651–1658

    Article  PubMed  CAS  Google Scholar 

  • 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 13:2367–2373

    Article  PubMed  CAS  Google Scholar 

  • 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 281:2215–2224

    Article  PubMed  CAS  Google Scholar 

  • 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 108:1505–1512

    PubMed  CAS  Google Scholar 

  • 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 8:771–780

    Article  PubMed  CAS  Google Scholar 

  • 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 159:291–302

    Article  PubMed  CAS  Google Scholar 

  • Lessmann E, Leitges M, Huber M (2006) A redundant role for PKC-ε in mast cell signaling and effector function. Int Immunol 18:767–773

    Article  PubMed  CAS  Google Scholar 

  • Li L, Tucker RW, Hennings H, Yuspa SH (1995a) Chelation of intracellular Ca2+ inhibits murine keratinocyte differentiation in vitro. J Cell Physiol 163:105–114

    Article  PubMed  CAS  Google Scholar 

  • 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 6:1171–1184

    PubMed  CAS  Google Scholar 

  • 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 19:8547–8558

    PubMed  CAS  Google Scholar 

  • 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 33:684–694

    Article  PubMed  CAS  Google Scholar 

  • 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 63:1153–1156

    PubMed  CAS  Google Scholar 

  • 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 27:8480–8491

    Article  PubMed  CAS  Google Scholar 

  • Matsui MS, Wang N, DeLeo VA (1996) Ultraviolet radiation B induces differentiation and protein kinase C in normal human epidermal keratinocytes. Photodermatol Photoimmunol Photomed 12:103–108

    PubMed  CAS  Google Scholar 

  • 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 303:350–356

    Article  PubMed  CAS  Google Scholar 

  • 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 13:1113–1120

    Article  PubMed  CAS  Google Scholar 

  • 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 416:865–869

    Article  PubMed  CAS  Google Scholar 

  • 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 5:828–831

    Article  PubMed  CAS  Google Scholar 

  • 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 17:1475–1486

    Article  PubMed  CAS  Google Scholar 

  • 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 36:1147–1153

    Article  PubMed  CAS  Google Scholar 

  • 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 18:5199–5207

    PubMed  CAS  Google Scholar 

  • 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 66:9379–9384

    Article  PubMed  CAS  Google Scholar 

  • Pierceall WE, Goldberg LH, Tainsky MA, Mukhopadhyay T, Ananthaswamy HN (1991) Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog 4:196–202

    Article  PubMed  CAS  Google Scholar 

  • 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 212:54–67

    Article  PubMed  CAS  Google Scholar 

  • Punnonen K, Yuspa SH (1992) Ultraviolet light irradiation increases cellular diacylglycerol and induces translocation of diacylglycerol kinase in murine keratinocytes. J Invest Dermatol 99:221–226

    Article  PubMed  CAS  Google Scholar 

  • Quintanilla M, Brown K, Ramsden M, Balmain A (1986) Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322:78–80

    Article  PubMed  CAS  Google Scholar 

  • 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 59:5710–5718

    PubMed  CAS  Google Scholar 

  • 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 60:595–602

    PubMed  CAS  Google Scholar 

  • 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 323:822–824

    Article  PubMed  CAS  Google Scholar 

  • Rosette C, Karin M (1996) Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors. Science 274:1194–1197

    Article  PubMed  CAS  Google Scholar 

  • 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 13:167–176

    PubMed  CAS  Google Scholar 

  • 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 280:35310–35317

    Article  PubMed  CAS  Google Scholar 

  • 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 164:979–984

    Article  PubMed  CAS  Google Scholar 

  • 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 102:13921–13926

    Article  PubMed  CAS  Google Scholar 

  • 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 11:43–49

    Article  PubMed  CAS  Google Scholar 

  • 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 65:5720–5729

    Article  PubMed  CAS  Google Scholar 

  • 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 18:790–798

    PubMed  CAS  Google Scholar 

  • 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 95:2307–2312

    Article  PubMed  CAS  Google Scholar 

  • Seitz CS, Deng H, Hinata K, Lin Q, Khavari PA (2000) Nuclear factor kappaB subunits induce epithelial cell growth arrest. Cancer Res 60:4085–4092

    PubMed  CAS  Google Scholar 

  • 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 36:292–299

    PubMed  CAS  Google Scholar 

  • 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 17:2555–2563

    Article  PubMed  CAS  Google Scholar 

  • 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 123:434–443

    Article  PubMed  CAS  Google Scholar 

  • 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):29703–29710

    Article  PubMed  CAS  Google Scholar 

  • 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 34:71–79

    Article  PubMed  CAS  Google Scholar 

  • Soehnge H, Ouhtit A, Ananthaswamy ON (1997) Mechanisms of induction of skin cancer by UV radiation. Front Biosci 2:d538–d551

    PubMed  CAS  Google Scholar 

  • 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 131:796–800

    Article  PubMed  CAS  Google Scholar 

  • 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 214:888–894

    Article  PubMed  CAS  Google Scholar 

  • 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 110:218–223

    Article  PubMed  CAS  Google Scholar 

  • Takeda K, Takeuchi O, Tsujimura T, Itami S, Adachi O, Kawai T et al (1999) Limb and skin abnormalities in mice lacking IKKα. Science 284:313–316

    Article  PubMed  CAS  Google Scholar 

  • 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 53:4803–4810

    PubMed  CAS  Google Scholar 

  • Tibudan SS, Wang Y, Denning MF (2002) Activation of protein kinase C triggers irreversible cell cycle withdrawal in human keratinocytes. J Invest Dermatol 119:1282–1289

    Article  PubMed  CAS  Google Scholar 

  • Tu CL, Chang W, Bikle DD (2001) The extracellular calcium-sensing receptor is required for calcium-induced differentiation in human keratinocytes. J Biol Chem 276:41079–41085

    Article  PubMed  CAS  Google Scholar 

  • 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 283:3519–3528

    Article  PubMed  CAS  Google Scholar 

  • 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 271:9790–9794

    Article  PubMed  CAS  Google Scholar 

  • 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 271:23512–23519

    Article  PubMed  CAS  Google Scholar 

  • 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 42:29–39

    Article  PubMed  CAS  Google Scholar 

  • 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 46:3926

    Google Scholar 

  • 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 45:381–388

    Article  PubMed  CAS  Google Scholar 

  • 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 65:2811–2817

    Article  PubMed  CAS  Google Scholar 

  • 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 112:3497–3506

    PubMed  CAS  Google Scholar 

  • 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 59:860–866

    PubMed  CAS  Google Scholar 

  • 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 21:3620–3630

    Article  PubMed  CAS  Google Scholar 

  • 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 63:6547–6555

    PubMed  CAS  Google Scholar 

  • 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 64:7756–7765

    Article  PubMed  CAS  Google Scholar 

  • 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 81:9–18

    Article  PubMed  CAS  Google Scholar 

  • 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 65:7071–7080

    Article  PubMed  CAS  Google Scholar 

  • 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 282:8695–8703

    Article  PubMed  CAS  Google Scholar 

  • 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 20:1695–1704

    Article  PubMed  CAS  Google Scholar 

  • 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 19:2088–2097

    Article  PubMed  CAS  Google Scholar 

  • 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 195:249–259

    Article  PubMed  CAS  Google Scholar 

  • Yoshida K (2007) PKCδ signaling: Mechanisms of DNA damage response and apoptosis. Cell Signal 19:892–901

    Article  PubMed  CAS  Google Scholar 

  • 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 281:5734–5740

    Article  PubMed  CAS  Google Scholar 

  • 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 245:514–518

    Article  PubMed  CAS  Google Scholar 

  • 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 262:402–404

    Article  PubMed  CAS  Google Scholar 

  • Yuspa SH, Kilkenny AE, Stanley J, Lichti U (1985) Keratinocytes blocked in phorbol ester-responsive early stage of terminal differentiation by sarcoma viruses. Nature 314:459–462

    Article  PubMed  CAS  Google Scholar 

  • 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 272:13275–13280

    Article  PubMed  CAS  Google Scholar 

  • 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 26:249–257

    Article  PubMed  CAS  Google Scholar 

  • 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 128:833–845

    Article  PubMed  CAS  Google Scholar 

  • 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 372:773–776

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

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

Author information

Authors and Affiliations

  1. Department of Pathology, Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, USA

    Mitchell F. Denning

Authors
  1. Mitchell F. Denning
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mitchell F. Denning .

Editor information

Editors and Affiliations

  1. Center for Molecular Toxicology &, Carcinogenesis, Pennsylvania State University, University Park, 16801, Pennsylvania, USA

    Adam B. Glick

  2. National Institute on Deafness &, Other Communication Disorders, National Institute of Health, Bethesda, 20892, Maryland, USA

    Carter Van Waes

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Denning, M.F. (2011). Protein Kinase C and the Development of Squamous Cell Carcinoma. In: Glick, A., Waes, C. (eds) Signaling Pathways in Squamous Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7203-3_8

Download citation

Publish with us

Policies and ethics

Search

Navigation