Interacting Signaling Pathways in Mouse Skin Tumor Initiation and Progression

  • Christophe Cataisson
  • Stuart H. Yuspa


The multistage induction of squamous cell cancer (SCC) on mouse skin as a consequence of chemical exposures has remarkable phenotypic and genotypic homology to human SCC development. Genetically altered mouse models have been instrumental in defining the respective contribution of signaling pathways on the development of SCC in vivo. Central to the skin carcinogenesis process is the activation of the EGFR-Ras-MAPK pathway. While hyperactivation of the pathway can often be attributed to activating mutations in ras genes, it appears that for the majority of cases the pathway is activated by alterations in upstream modulators as well as downstream effectors that are integral to the altered phenotype of the initiated keratinocytes. This chapter will review data from experimental inductions of cutaneous SCC with a special emphasis on mouse models. Particularly, the role of the EGFR-Ras-MAPK pathway, protein kinase C, nuclear factor kappa B and the expression of proinflammatory factors by transformed keratinocyte will be covered in more detail.


Epidermal Growth Factor Receptor KRAS Mutation Squamous Cell Carcinoma Epidermal Growth Factor Receptor Inhibitor Skin Carcinogenesis 
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.


  1. Abel EL, Angel JM, Kiguchi K, DiGiovanni J (2009) Multi-stage chemical carcinogenesis in mouse skin: fundamentals and applications. Nat Protoc 4:1350–1362CrossRefPubMedGoogle Scholar
  2. Acosta JC, O’Loghlen A, Banito A et al. (2008) Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133:1006–1018CrossRefPubMedGoogle Scholar
  3. Ancrile B, Lim KH, Counter CM (2007) Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev 21:1714–1719CrossRefPubMedGoogle Scholar
  4. Aoki Y, Niihori T, Kawame H, Kurosawa K et al. (2005) Germline mutations in HRAS ­proto-oncogene cause Costello syndrome. Nat Genet 37:1038–1040CrossRefPubMedGoogle Scholar
  5. Arnott CH, Scott KA, Moore RJ et al. (2002) Tumour necrosis factor-alpha mediates tumour ­promotion via a PKC alpha- and AP-1-dependent pathway. Oncogene 21:4728–4738CrossRefPubMedGoogle Scholar
  6. Arnott CH, Scott KA, Moore RJ, Robinson SC, Thompson RG, Balkwill FR (2004) Expression of both TNF-alpha receptor subtypes is essential for optimal skin tumour development. Oncogene 23:1902–1910CrossRefPubMedGoogle Scholar
  7. Aziz MH, Manoharan HT, Verma AK (2007) Protein kinase C epsilon, which sensitizes skin to sun’s UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3. Cancer Res 67:1385–1394CrossRefPubMedGoogle Scholar
  8. Bai Y, Edamatsu H, Maeda S, Saito H, Suzuki N, Satoh T, Kataoka T (2004) Crucial role of phospholipase Cepsilon in chemical carcinogen-induced skin tumor development. Cancer Res 64:8808–8810CrossRefPubMedGoogle Scholar
  9. Balmain A, Ramsden M, Bowden GT, Smith J (1984) Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307:658–660CrossRefPubMedGoogle Scholar
  10. Bignell GR, Warren W, Seal S et al. (2000) Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 25:160–165CrossRefPubMedGoogle Scholar
  11. Bos JL (1989) ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689PubMedGoogle Scholar
  12. Bourcier C, Jacquel A, Hess J et al. (2006) p44 mitogen-activated protein kinase (extracellular signal-regulated kinase 1)-dependent signaling contributes to epithelial skin carcinogenesis. Cancer Res 66:2700–2707CrossRefPubMedGoogle Scholar
  13. Breitkreutz D, Braiman-Wiksman L, Daum N, Denning MF, Tennenbaum T (2007) Protein kinase C family: on the crossroads of Cell signaling in skin and tumor epithelium. J Cancer Res Clin Oncol 133:793–808CrossRefPubMedGoogle Scholar
  14. Budunova IV, Perez P, Vaden VR, Spiegelman VS, Slaga TJ, Jorcano JL (1999) Increased expression of p50-NF-kappaB and constitutive activation of NF- kappaB transcription factors during mouse skin carcinogenesis. Oncogene 18:7423–7431CrossRefPubMedGoogle Scholar
  15. Campbell C, Quinn AG, Rees JL (1993) Codon 12 Harvey-ras mutations are rare events in non-melanoma human skin cancer. Br J Dermatol 128:111–114CrossRefPubMedGoogle Scholar
  16. Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y (1982) Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 257:7847–7851PubMedGoogle Scholar
  17. Cataisson C, Joseloff E, Murillas R et al. (2003) Activation of cutaneous protein kinase C alpha induces keratinocyte apoptosis and intraepidermal inflammation by independent signaling pathways. J Immunol 171:2703–2713PubMedGoogle Scholar
  18. Cataisson C, Pearson AJ, Tsien MZ, Mascia F, Gao JL, Pastore S, Yuspa SH (2006) CXCR2 ligands and G-CSF mediate PKCalpha-induced intraepidermal inflammation. J Clin Invest 116:2757–2766CrossRefPubMedGoogle Scholar
  19. Cataisson C, Ohman R, Patel G et al. (2009) Inducible cutaneous inflammation reveals a protumorigenic role for keratinocyte CXCR2 in skin carcinogenesis. Cancer Res 69:319–328CrossRefPubMedGoogle Scholar
  20. Chan KS, Sano S, Kiguchi K, Anders J, Komazawa N, Takeda J, DiGiovanni J (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
  21. Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174CrossRefPubMedGoogle Scholar
  22. D’Costa AM, Robinson JK, Maududi T, Chaturvedi V, Nickoloff BJ, Denning MF (2006) The proapoptotic tumor suppressor protein kinase C-delta is lost in human squamous cell carcinomas. Oncogene 25:378–386PubMedGoogle Scholar
  23. Dajee M, Lazarov M, Zhang JY et al. (2003) NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421:639–643CrossRefPubMedGoogle Scholar
  24. Denning MF, Dlugosz AA, Howett MK, Yuspa SH (1993) Expression of an oncogenic rasHa gene in murine keratinoctyes induces tyrosine phosphorylation and reduced activity of protein kinase. C J Biol Chem 268:26079–26081Google Scholar
  25. 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 J Biol Chem 271:5325–5331Google Scholar
  26. Dhawan P, Richmond A (2002) Role of CXCL1 in tumorigenesis of melanoma. J Leukoc Biol 72:9–18PubMedGoogle Scholar
  27. 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-alpha. Cancer Res 54:6413–6420, STPubMedGoogle Scholar
  28. Dlugosz AA, Cheng C, Williams EK et al. (1995) Autocrine transforming growth factor is dispensible for v-ras Ha-induced epidermal neoplasia: potential involvement of alternate epidermal growth factor receptor ligands. Cancer Res 55:1883–1893PubMedGoogle Scholar
  29. Dlugosz AA, Hansen L, Cheng C et al. (1997) Targeted disruption of the epidermal growth factor receptor impairs growth of squamous papillomas expressing the v-ras Ha oncogene but does not block in vitro keratinocyte responses to oncogenic ras. Cancer Res 57:3180–3188PubMedGoogle Scholar
  30. Dominey AM, Wang XJ, King LE Jr et al. (1993) Targeted overexpression of transforming growth factor alpha in the epidermis of transgenic mice elicits hyperplasia, hyperkeratosis, and spontaneous, squamous papillomas. Cell Growth Differ 4:1071–1082PubMedGoogle Scholar
  31. Ebinu JO, Bottorff DA, Chan EY, Stang SL, Dunn RJ, Stone JC (1998) RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. Science 280:1082–1086CrossRefPubMedGoogle Scholar
  32. Ehrenreiter K, Kern F, Velamoor V, Meissl K, Galabova-Kovacs G, Sibilia M, Baccarini M (2009) Raf-1 addiction in Ras-induced skin carcinogenesis. Cancer Cell 16:149–160CrossRefPubMedGoogle Scholar
  33. Estep AL, Tidyman WE, Teitell MA, Cotter PD, Rauen KA (2006) HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A 140:8–16PubMedGoogle Scholar
  34. Glick AB, Sporn MB, Yuspa SH (1991) Altered regulation of TGF 1 and TGF in primary keratinocytes and papillomas expressing v-Ha-ras. Mol Carcinog 4:210–219CrossRefPubMedGoogle Scholar
  35. Gonzalez-Garcia A, Pritchard CA, Paterson HF, Mavria G, Stamp G, Marshall CJ (2005) RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 7:219–226CrossRefPubMedGoogle Scholar
  36. Griner EM, Kazanietz MG (2007) Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 7:281–294CrossRefPubMedGoogle Scholar
  37. Gupta S, Ramjaun AR, Haiko P, Wang Y, Warne PH, Nicke B, Nye E, Stamp G, Alitalo K, Downward J (2007) Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell 129:957–968CrossRefPubMedGoogle Scholar
  38. Hansen LA, Alexander N, Hogan ME et al. (1997) Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development. Am J Pathol 150:1959–1975PubMedGoogle Scholar
  39. Hansen LA, Woodson RL II, Holbus S, Strain K, Lo Y-C, Yuspa SH (2000) The epidermal growth factor receptor is required to maintain the proliferative population in the basal compartment of epidermal tumors. Cancer Res 60:3328–3332PubMedGoogle Scholar
  40. Harari PM (2004) Epidermal growth factor receptor inhibition strategies in oncology. Endocr Relat Cancer 11:689–708CrossRefPubMedGoogle Scholar
  41. Hennings H, Glick AB, Lowry DT, Krsmanovic LS, Sly LM, Yuspa SH (1993) FVB/N mice: an inbred strain sensitive to the chemical induction of squamous cell carcinomas in the skin. Carcinogenesis 14:2353–2358CrossRefPubMedGoogle Scholar
  42. Ise K, Nakamura K, Nakao K et al. (2000) Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis. Oncogene 19:2951–2956CrossRefPubMedGoogle Scholar
  43. Jansen AP, Dreckschmidt NE, Verwiebe EG, Wheeler DL, Oberley TD, Verma AK (2001) 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 93:635–643CrossRefPubMedGoogle Scholar
  44. Joseloff E, Cataisson C, Aamodt H, Ocheni H, Blumberg P, Kraker AJ, Yuspa SH (2002) Src ­family kinases phosphorylate protein kinase C delta on tyrosine residues and modify the neoplastic phenotype of skin keratinocytes. J Biol Chem 277:12318–12323CrossRefPubMedGoogle Scholar
  45. Kelley GG, Reks SE, Ondrako JM, Smrcka AV (2001) Phospholipase C(epsilon): a novel Ras effector. EMBO J 20:743–754CrossRefPubMedGoogle Scholar
  46. Kiguchi K, Beltran L, Rupp T, DiGiovanni J (1998) Altered expression of epidermal growth factor receptor ligands in tumor promoter-treated mouse epidermis and in primary mouse skin tumors induced by an initiation-promotion protocol. Mol Carcinog 22:73–83CrossRefPubMedGoogle Scholar
  47. Kreimer-Erlacher H, Seidl H, Back B, Kerl H, Wolf P (2001) High mutation frequency at Ha-ras exons 1-4 in squamous Cell carcinomas from PUVA-treated psoriasis patients. Photochem Photobiol 74:323–330CrossRefPubMedGoogle Scholar
  48. Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807–869PubMedGoogle Scholar
  49. Lazarov M, Kubo Y, Cai T et al. (2002) CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Nat Med 8:1105–1114CrossRefPubMedGoogle Scholar
  50. Leach KL, James ML, Blumberg PM (1983) Characterization of a specific phorbol ester aporeceptor in mouse brain cytosol. Proc Natl Acad Sci USA 80:4208–4212CrossRefPubMedGoogle Scholar
  51. Li L, Lorenzo PS, Bogi K, Blumberg PM, Yuspa SH (1999) Protein kinase C 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
  52. Lind MH, Rozell B, Wallin RP, van Hogerlinden M, Ljunggren HG, Toftgard R, Sur I (2004) Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-kappaB inhibition. Proc Natl Acad Sci USA 101:4972–4977CrossRefPubMedGoogle Scholar
  53. Liu B, Park E, Zhu F, Bustos T, Liu J, Shen J, Fischer SM, Hu Y (2006) A critical role for I kappaB kinase alpha in the development of human and mouse squamous cell carcinomas. Proc Natl Acad Sci USA 103:17202–17207CrossRefPubMedGoogle Scholar
  54. Liu B, Xia X, Zhu F et al. (2008) IKKalpha is required to maintain skin homeostasis and prevent skin cancer. Cancer Cell 14:212–225CrossRefPubMedGoogle Scholar
  55. Loercher A, Lee TL, Ricker JL et al. (2004) Nuclear factor-kappaB is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma. Cancer Res 64:6511–6523CrossRefPubMedGoogle Scholar
  56. Loukinova E, Dong G, Enamorado-Ayalya I, Thomas GR, Chen Z, Schreiber H, Van Waes C (2000) Growth regulated Oncogene-alpha expression by murine squamous cell carcinoma promotes tumor growth, metastasis, leukocyte infiltration and angiogenesis by a host CXC receptor-2 dependent mechanism. Oncogene 19:3477–3486CrossRefPubMedGoogle Scholar
  57. Mackay HJ, Twelves CJ (2007) Targeting the protein kinase C family: are we there yet? Nat Rev Cancer 7:554–562CrossRefPubMedGoogle Scholar
  58. Malliri A, van der Kammen RA, Clark K, Van DV, Michiels F, Collard JG (2002) Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417:867–871CrossRefPubMedGoogle Scholar
  59. Martin-Oliva D, O’Valle F, Munoz-Gamez JA et al. (2004) Crosstalk between PARP-1 and NF-kappaB modulates the promotion of skin neoplasia. Oncogene 23:5275–5283CrossRefPubMedGoogle Scholar
  60. Mascia F, Mariani V, Girolomoni G, Pastore S (2003) Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation. Am J Pathol 163:303–312PubMedGoogle Scholar
  61. Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fassler R (2006) Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 125:665–677CrossRefPubMedGoogle Scholar
  62. Moore RJ, Owens DM, Stamp G et al. (1999) Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 5:828–831CrossRefPubMedGoogle Scholar
  63. Mueller MM (2006) Inflammation in epithelial skin tumours: old stories and new ideas. Eur J Cancer 42:735–744CrossRefPubMedGoogle Scholar
  64. Muller A, Sonkoly E, Eulert C et al. (2006) Chemokine receptors in head and neck cancer: association with metastatic spread and regulation during chemotherapy. Int J Cancer 118:2147–2157CrossRefPubMedGoogle Scholar
  65. Nibbs RJ, Gilchrist DS, King V, Ferra A, Forrow S, Hunter KD, Graham GJ (2007) The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors. J Clin Invest 117:1884–1892CrossRefPubMedGoogle Scholar
  66. Oki-Idouchi CE, Lorenzo PS (2007) Transgenic overexpression of RasGRP1 in mouse epidermis results in spontaneous tumors of the skin. Cancer Res 67:276–280CrossRefPubMedGoogle Scholar
  67. Oster H, Leitges M (2006) Protein kinase C alpha but not PKCzeta suppresses intestinal tumor formation in ApcMin/+ mice. Cancer Res 66:6955–6963CrossRefPubMedGoogle Scholar
  68. Park E, Zhu F, Liu B, Xia X, Shen J, Bustos T, Fischer SM, Hu Y (2007) Reduction in IkappaB kinase alpha expression promotes the development of skin papillomas and carcinomas. Cancer Res 67:9158–9168CrossRefPubMedGoogle Scholar
  69. Pasparakis M, Courtois G, Hafner M, Schmidt-Supprian M, Nenci A, Toksoy A, Krampert M, Goebeler M, Gillitzer R, Israel A, Krieg T, Rajewsky K, Haase I (2002) TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417:861–866CrossRefPubMedGoogle Scholar
  70. Pastore S, Mascia F, Mariotti F, Dattilo C, Mariani V, Girolomoni G (2005) ERK1/2 regulates epidermal chemokine expression and skin inflammation. J Immunol 174:5047–5056PubMedGoogle Scholar
  71. Pastore S, Mascia F, Mariani V, Girolomoni G (2008) The epidermal growth factor receptor system in skin repair and inflammation. J Invest Dermatol 128:1365–1374CrossRefPubMedGoogle Scholar
  72. Pierceall WE, Goldberg LH, Tainsky MA, Mukhopadhyay T, Ananthaswamy HN (1991) Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog 4:196–202CrossRefPubMedGoogle Scholar
  73. Pikarsky E, Ben-Neriah Y (2006) NF-kappaB inhibition: a double-edged sword in cancer? Eur J Cancer 42:779–784CrossRefPubMedGoogle Scholar
  74. Pivarcsi A, Muller A, Hippe A et al. (2007) Tumor immune escape by the loss of homeostatic chemokine expression. Proc Natl Acad Sci USA 104:19055–19060CrossRefPubMedGoogle Scholar
  75. Reddig PJ, Dreckschmidt NE, Ahrens H et al. (1999) Transgenic mice overexpressing protein kinase Cdelta in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 59:5710–5718PubMedGoogle Scholar
  76. Reddig PJ, Dreckschmidt NE, Zou J, Bourguignon SE, Oberley TD, Verma AK (2000) Transgenic mice overexpressing protein kinase C epsilon in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion. Cancer Res 60:595–602PubMedGoogle Scholar
  77. Repertinger SK, Campagnaro E, Fuhrman J, El Abaseri T, Yuspa SH, Hansen LA (2004) EGFR enhances early healing after cutaneous incisional wounding. J Invest Dermatol 123:982–989CrossRefPubMedGoogle Scholar
  78. Roop DR, Lowy DR, Tambourin PE et al. (1986) An activated Harvey ras oncogene produces benign tumours on mouse epidermal tissue. Nature 323:822–824CrossRefPubMedGoogle Scholar
  79. Rumsby G, Carter RL, Gusterson BA (1990) Low incidence of ras oncogene activation in human squamous cell carcinomas. Br J Cancer 61:365–368PubMedGoogle Scholar
  80. Scholl FA, Dumesic PA, Barragan DI, Charron J, Khavari PA (2009a) Mek1/2 gene dosage determines tissue response to oncogenic Ras signaling in the skin. Oncogene 28:1485–1495CrossRefPubMedGoogle Scholar
  81. Scholl FA, Dumesic PA, Barragan DI, Harada K, Charron J, Khavari PA (2009b) Selective role for Mek1 but not Mek2 in the induction of epidermal neoplasia. Cancer Res 69:3772–3778CrossRefPubMedGoogle Scholar
  82. Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295–308CrossRefPubMedGoogle Scholar
  83. Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–458CrossRefPubMedGoogle Scholar
  84. 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 131:796–800CrossRefPubMedGoogle Scholar
  85. Stone JC (2006) Regulation of Ras in lymphocytes: get a GRP. Biochem Soc Trans 34:858–861CrossRefPubMedGoogle Scholar
  86. Sur I, Ulvmar M, Toftgard R (2008) The two-faced NF-kappaB in the skin. Int Rev Immunol 27:205–223CrossRefPubMedGoogle Scholar
  87. Threadgill DW, Dlugosz AA, Hansen LA et al. (1995) Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269:230–234CrossRefPubMedGoogle Scholar
  88. van Hogerlinden M, Rozell BL, Ahrlund-Richter L, Toftgard R (1999) Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kappaB signaling. Cancer Res 59:3299–3303PubMedGoogle Scholar
  89. van Hogerlinden M, Auer G, Toftgard R (2002) Inhibition of Rel/Nuclear Factor-kappaB signaling in skin results in defective DNA damage-induced cell cycle arrest and Ha-ras- and p53-­independent tumor development. Oncogene 21:4969–4977CrossRefPubMedGoogle Scholar
  90. Vandercappellen J, Van DJ, Struyf S (2008) The role of CXC chemokines and their receptors in cancer. Cancer Lett 267:226–244CrossRefPubMedGoogle Scholar
  91. Vassar R, Hutton ME, Fuchs E (1992) Transgenic overexpression of transforming growth factor bypasses the need for c-Ha-ras mutations in mouse skin tumorigenesis. Mol Cell Biol 12:4643–4653PubMedGoogle Scholar
  92. Wang HQ, Smart RC (1999) Overexpression of protein kinase C-alpha 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(Pt 20):3497–3506PubMedGoogle Scholar
  93. Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14:6735–6741CrossRefPubMedGoogle Scholar
  94. Yan J, Roy S, Apolloni A, Lane A, Hancock JF (1998) Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J Biol Chem 273:24052–24056CrossRefPubMedGoogle Scholar
  95. Yang G, Rosen DG, Zhang Z et al. (2006) The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc Natl Acad Sci USA 103:16472–16477CrossRefPubMedGoogle Scholar
  96. Zhang JY, Tao S, Kimmel R, Khavari PA (2005) CDK4 regulation by TNFR1 and JNK is required for NF-kappaB-mediated epidermal growth control. J Cell Biol 168:561–566CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Laboratory of Cancer Biology and Genetics, National Cancer InstituteNIHBethesdaUSA

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