J Leukoc Biol 72(1): 9-18

Role of CXCL1 in tumorigenesis of melanoma

^{Department of Veterans Affairs, Nashville, Tennessee}

^{Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee}

Correspondence: Ann Richmond, Department of Cancer Biology, Vanderbilt University School of Medicine, MCN T-2212, Nashville, TN 37232. E-mail: ude.tlibrednav.liamcm@dnomhcir.nna

Abstract

The CXC chemokine, CXCL1 (melanoma growth-stimulatory activity/growth-regulated protein α), plays a major role in inflammation, angiogenesis, tumorigenesis, and wound healing. Recently, chemokines have been extensively related to cellular transformation, tumor growth, homing, and metastasis. CXCL1 and its mouse homologue MIP-2 have been shown to be involved in the process of tumor formation. When chemokines such as CXCL1 and CXCL8 (IL-8) become disregulated so that they are chronically expressed, tissue damage, angiogenesis, and tumorigenesis can follow. This up-regulation of chemokines has been attributed to constitutive activation of NF-κB. The constitutive NF-κB activation is an emerging hallmark in various types of tumors including breast, colon, pancreatic, ovarian, as well as melanoma. Previous findings from our laboratory and other laboratories have demonstrated the role of endogenous activation of NF-κB in association with enhanced metastatic potential of malignant melanoma cells and suggest that targeting NF-κB may have potential therapeutic effects in clinical trials. An important step in this direction would be to delineate the important intracellular pathways and upstream kinases involved in up-regulation of NF-κB in melanoma cells. In this review, the signaling pathways involved in the disregulation of NF-κB and chemokine expression are discussed.

Keywords: chemokines, NF-κB, signaling

Abstract

References

1. Baggiolini MChemokines and leukocyte traffic. Nature. 1998;392:565–568.[PubMed][Google Scholar]
2. Schall TJ, Bacon KBChemokines, leukocyte trafficking and inflammation. Curr Opin Immunol. 1994;6:865–873.[PubMed][Google Scholar]
3. Cyster JGChemokines and cell migration in secondary lymphoid organs. Science. 1999;286:2098–2102.[PubMed][Google Scholar]
4. Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, Burdick MD, Strieter RMCXC chemokines in angiogenesis. J Leukoc Biol. 2000;68:1–8.[PubMed][Google Scholar]
5. Wang JM, Deng X, Gong W, Su SChemokines and their role in tumor growth and metastasis. J Immunol Methods. 1998;220:1–17.[PubMed][Google Scholar]
6. Sallusto F, Mackay CR, Lanzavecchia AThe role of chemokine receptors in primary, effector, and memory immune responses Annu. Rev Immunol. 2000;18:593–620.[PubMed][Google Scholar]
7. Rossi D, Zlotnik AThe biology of chemokines and their receptors. Annu Rev Immunol. 2000;18:217–242.[PubMed][Google Scholar]
8. Rollins BJChemokines. Blood. 1997;90:909–928.[PubMed][Google Scholar]
9. Strieter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J, Dzuiba J, Van Damme J, Walz A, Marriott D, et al The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem. 1995;270:27348–27357.[PubMed][Google Scholar]
10. Yoneda J, Kuniyasu H, Crispens MA, Price JE, Bucana CD, Fidler IJExpression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. J Natl Cancer Inst. 1998;90:447–454.[PubMed][Google Scholar]
11. Huang M, Wang J, Lee P, Sharma S, Mao JT, Meissner H, Uyemura K, Modlin R, Wollman J, Dubinett SMHuman non-small cell lung cancer cells express a type 2 cytokine pattern. Cancer Res. 1995;55:3847–3853.[PubMed][Google Scholar]
12. Arenberg DA, Kunkel SL, Polverini PJ, Morris SB, Burdick MD, Glass MC, Taub DT, Iannettoni MD, Whyte RI, Strieter RMInterferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases. J Exp Med. 1996;184:981–992.[Google Scholar]
13. Murdoch C, Finn AChemokine receptors and their role in inflammation and infectious diseases. Blood. 2000;95:3032–3043.[PubMed][Google Scholar]
14. Wells TN, Proudfoot AEChemokine receptors and their antagonists in allergic lung disease. Inflamm Res. 1999;48:353–362.[PubMed][Google Scholar]
15. Yamamoto J, Adachi Y, Onoue Y, Kanegane H, Miyawaki T, Toyoda M, Seki T, Morohashi MCD30 expression on circulating memory CD4+ T cells as a Th2-dominated situation in patients with atopic dermatitis. Allergy. 2000;55:1011–1018.[PubMed][Google Scholar]
16. Mach FThe role of chemokines in atherosclerosis. Curr Atheroscler Rep. 2001;3:243–251.[PubMed][Google Scholar]
17. Tkachuk AN, Moormann AM, Poore JA, Rochford RA, Chensue SW, Mwapasa V, Meshnick SRMalaria enhances expression of CC chemokine receptor 5 on placental macrophages. J Infect Dis. 2001;183:967–972.[PubMed][Google Scholar]
18. Loetscher P, Moser B, Baggiolini MChemokines and their receptors in lymphocyte traffic and HIV infection. Adv Immunol. 2000;74:127–180.[PubMed][Google Scholar]
19. International Union of Immunological Societies/World Health Organization Subcommittee on Chemokine NomenclatureChemokine/chemokine receptor nomenclature. J Leukoc Biol. 2001;70:465–466.[PubMed][Google Scholar]
20. Tang T, Owen JD, Du J, Walker CL, Richmond AMolecular cloning and characterization of a mouse gene with homology to the Duffy-antigen receptor for chemokines. DNA Seq. 1998;9:129–143.[PubMed][Google Scholar]
21. Yang YT, Chen SC, Leach MW, Manfra D, Homey B, Wiekowski M, Sullivan L, Jenh CH, Narula SK, Chensue SW, Lira SATransgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi’s sarcoma. J Exp Med. 2000;191:445–454.[Google Scholar]
22. Rosenkilde MM, Waldhoer M, Lüttichau HR, Schwartz TW, Rosenkilde MMVirally encoded 7TM receptors. Oncogene. 2001;20:1582–1593.[PubMed][Google Scholar]
23. Strieter RMChemokines: not just leukocyte chemoattractants in the promotion of cancer. Nat Immunol. 2001;2:285–286.[PubMed][Google Scholar]
24. Gershengorn MC, Geras-Raaka E, Varma A, Clark-Lewis IChemokines activate Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture. J Clin Investig. 1998;102:1469–1472.[Google Scholar]
25. Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn MC, Cesarman EHuman herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature. 1997;385:347–350.[PubMed][Google Scholar]
26. Burger M, Burger JA, Hoch RC, Oades Z, Takamori H, Schraufstatter IUPoint mutation causing constitutive signaling of CXCR2 leads to transforming activity similar to Kaposi’s sarcoma herpesvirus-G protein-coupled receptor. J Immunol. 1999;163:2017–2022.[PubMed][Google Scholar]
27. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik AInvolvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–56.[PubMed][Google Scholar]
28. Mohle R, Schittenhelm M, Failenschmid C, Bautz F, Kratz-Albers K, Serve H, Brugger W, Kanz LFunctional response of leukaemic blasts to stromal cell-derived factor-1 correlates with preferential expression of the chemokine receptor CXCR4 in acute myelomonocytic and lymphoblastic leukaemia. Br J Haematol. 2000;110:563–572.[PubMed][Google Scholar]
29. Mohle R, Failenschmid C, Bautz F, Kanz LOverexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1) Leukemia. 1999;13:1954–1959.[PubMed][Google Scholar]
30. Arai J, Yasukawa M, Yakushijin Y, Miyazaki T, Fujita SStromal cells in lymph nodes attract B-lymphoma cells via production of stromal cell-derived factor-1. Eur J Haematol. 2000;64:323–332.[PubMed][Google Scholar]
31. Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S, Kawaguchi M, Kobayashi H, Doi R, Hori T, Fujii N, Imamura MExpression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res. 2000;6:3530–3535.[PubMed][Google Scholar]
32. Scotton CJ, Wilson JL, Milliken D, Stamp G, Balkwill FREpithelial cancer cell migration: a role for chemokine receptors? Cancer Res. 2001;61:4961–4965.[PubMed][Google Scholar]
33. Moser B, Schumacher C, von Tscharner V, Clark-Lewis I, Baggiolini MNeutrophil-activating peptide 2 and gro/melanoma growth-stimulatory activity interact with neutrophil-activating peptide 1/interleukin 8 receptors on human neutrophils. J Biol Chem. 1991;266:10666–10671.[PubMed][Google Scholar]
34. Schumacher C, Clark-Lewis I, Baggiolini M, Moser BHigh- and low-affinity binding of GRO alpha and neutrophil-activating peptide 2 to interleukin 8 receptors on human neutrophils. Proc Natl Acad Sci USA. 1992;89:10542–10546.[Google Scholar]
35. Ahuja SK, Murphy PMThe CXC chemokines growth-regulated oncogene (GRO) alpha, GRObeta, GROgamma, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor. J Biol Chem. 1996;271:20545–20550.[PubMed][Google Scholar]
36. Richmond A, Thomas HGMelanoma growth stimulatory activity: isolation from human melanoma tumors and characterization of tissue distribution. J Cell Biochem. 1988;36:185–198.[PubMed][Google Scholar]
37. Bordoni R, Fine R, Murray D, Richmond ACharacterization of the role of melanoma growth stimulatory activity (MGSA) in the growth of normal melanocytes, nevocytes, and malignant melanocytes. J Cell Biochem. 1990;44:207–219.[PubMed][Google Scholar]
38. Chenevix-Trench G, Martin NG, Ellem KAGene expression in melanoma cell lines and cultured melanocytes: correlation between levels of c-src-1, c-myc and p53. Oncogene. 1990;5:1187–1193.[PubMed][Google Scholar]
39. Moser B, Barella L, Mattei S, Schumacher C, Boulay F, Colombo MP, Baggiolini MExpression of transcripts for two interleukin 8 receptors in human phagocytes, lymphocytes and melanoma cells. Biochem J. 1993;294:285–292.[Google Scholar]
40. Rodeck U, Melber K, Kath R, Menssen HD, Varello M, Atkinson B, Herlyn MConstitutive expression of multiple growth factor genes by melanoma cells but not normal melanocytes. J Investig Dermatol. 1991;97:20–26.[PubMed][Google Scholar]
41. Norgauer J, Metzner B, Schraufstatter IExpression and growth-promoting function of the IL-8 receptor beta in human melanoma cells. J Immunol. 1996;156:1132–1137.[PubMed][Google Scholar]
42. Devalaraja RM, Nanney LB, Du J, Qian Q, Yu Y, Devalaraja MN, Richmond ADelayed wound healing in CXCR2 knockout mice. J Investig Dermatol. 2000;115:234–244.[Google Scholar]
43. Haghnegahdar H, Du J, Wang D, Strieter RM, Burdick MD, Nanney LB, Cardwell N, Luan J, Shattuck-Brandt R, Richmond AThe tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma. J Leukoc Biol. 2000;67:53–62.[Google Scholar]
44. Owen JD, Strieter R, Burdick M, Haghnegahdar H, Nanney L, Shattuck-Brandt R, Richmond AEnhanced tumor-forming capacity for immortalized melanocytes expressing melanoma growth stimulatory activity/growth-regulated cytokine beta and gamma proteins. Int J Cancer. 1997;73:94–103.[PubMed][Google Scholar]
45. Balentien E, Mufson BE, Shattuck RL, Derynck R, Richmond AEffects of MGSA/GRO alpha on melanocyte transformation. Oncogene. 1991;6:1115–1124.[PubMed][Google Scholar]
46. Singh RK, Gutman M, Radinsky R, Bucana CD, Fidler IJExpression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res. 1994;54:3242–3247.[PubMed][Google Scholar]
47. Singh RK, Gutman M, Reich R, Bar-Eli MUltraviolet B irradiation promotes tumorigenic and metastatic properties in primary cutaneous melanoma via induction of interleukin 8. Cancer Res. 1995;55:3669–3674.[PubMed][Google Scholar]
48. Schadendorf D, Moller A, Algermissen B, Worm M, Sticherling M, Czarnetzki BMIL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J Immunol. 1993;151:2667–2675.[PubMed][Google Scholar]
49. Shelton RMSkin cancer: a review and atlas for the medical provider. Mt Sinai J Med. 2001;68:243–252.[PubMed][Google Scholar]
50. Anisowicz A, Messineo M, Lee SW, Sager RAn NF-kappa B-like transcription factor mediates IL-1/TNF-alpha induction of gro in human fibroblasts. J Immunol. 1991;147:520–527.[PubMed][Google Scholar]
51. Shattuck RL, Wood LD, Jaffe GJ, Richmond AMGSA/GRO transcription is differentially regulated in normal retinal pigment epithelial and melanoma cells. Mol Cell Biol. 1994;14:791–802.[Google Scholar]
52. Widmer U, Manogue KR, Cerami A, Sherry BGenomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta, members of the chemokine superfamily of proinflammatory cytokines. J Immunol. 1993;150:4996–5012.[PubMed][Google Scholar]
53. Ohmori Y, Fukumoto S, Hamilton TATwo structurally distinct kappa B sequence motifs cooperatively control LPS-induced KC gene transcription in mouse macrophages. J Immunol. 1995;155:3593–3600.[PubMed][Google Scholar]
54. Marx N, Mach F, Sauty A, Leung JH, Sarafi MN, Ransohoff RM, Libby P, Plutzky J, Luster ADPeroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells. J Immunol. 2000;164:6503–6508.[Google Scholar]
55. Wood LD, Richmond AConstitutive and cytokine-induced expression of the melanoma growth stimulatory activity/GRO alpha gene requires both NF-kappa B and novel constitutive factors. J Biol Chem. 1995;270:30619–30626.[PubMed][Google Scholar]
56. Wood LD, Farmer AA, Richmond AHMGI(Y) and Sp1 in addition to NF-kappa B regulate transcription of the MGSA/GRO alpha gene. Nucleic Acids Res. 1995;23:4210–4219.[Google Scholar]
57. Baldwin AS., Jr The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–683.[PubMed]
58. Stancovski I, Baltimore DNF-kappaB activation: the I kappaB kinase revealed? Cell. 1997;91:299–302.[PubMed][Google Scholar]
59. Karin MHow NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex. Oncogene. 1999;18:6867–6874.[PubMed][Google Scholar]
60. Regnier CH, Song HY, Cao Z, Rothe MIdentification and characterization of an IkappaB kinase. Cell. 1997;90:373–383.[PubMed][Google Scholar]
61. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin MACytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature. 1997;388:548–554.[PubMed][Google Scholar]
62. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin MThe IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell. 1997;91:243–252.[PubMed][Google Scholar]
63. Israel AThe IKK complex: an integrator of all signals that activate NF-kappaB? Trends Cell Biol. 2000;10:129–133.[PubMed][Google Scholar]
64. Li XH, Fang X, Gaynor RBRole of IKKgamma/nemo in assembly of the Ikappa B kinase complex. J Biol Chem. 2001;276:4494–4500.[PubMed][Google Scholar]
65. Malinin NL, Boldin MP, Kovalenko AV, Wallach DMAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. 1997;385:540–544.[PubMed][Google Scholar]
66. Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DVIkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science. 1997;278:866–869.[PubMed][Google Scholar]
67. Nakano H, Shindo M, Sakon S, Nishinaka S, Mihara M, Yagita H, Okumura KDifferential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc Natl Acad Sci USA. 1998;95:3537–3542.[Google Scholar]
68. Nemoto S, DiDonato JA, Lin ACoordinate regulation of IkappaB kinases by mitogen-activated protein kinase kinase kinase 1 and NF-kappaB-inducing kinase. Mol Cell Biol. 1998;18:7336–7343.[Google Scholar]
69. Madrid LV, Wang CY, Guttridge DC, Schottelius AJ, Baldwin AS, Jr, Mayo MWAkt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappaB. Mol Cell Biol. 2000;20:1626–1638.[Google Scholar]
70. Sizemore N, Leung S, Stark GRActivation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol Cell Biol. 1999;19:4798–4805.[Google Scholar]
71. Luan J, Shattuck-Brandt R, Haghnegahdar H, Owen JD, Strieter R, Burdick M, Nirodi C, Beauchamp D, Johnson KN, Richmond AMechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression. J Leukoc Biol. 1997;62:588–597.[PubMed][Google Scholar]
72. Nirodi C, NagDas S, Gygi SP, Olson G, Aebersold R, Richmond ARole for poly(ADP-ribose) polymerase in the transcriptional regulation of the melanoma growth stimulatory activity (CXCL1) gene expression. J Biol Chem. 2001;276:9366–9374.[Google Scholar]
73. Lindahl TRecognition and processing of damaged DNA. J Cell Sci Suppl. 1995;19:73–77.[PubMed][Google Scholar]
74. Berger NAPoly(ADP-ribose) in the cellular response to DNA damage. Radiat Res. 1985;101:4–15.[PubMed][Google Scholar]
75. Lindahl T, Satoh MS, Poirier GG, Klungland APost-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem Sci. 1995;20:405–411.[PubMed][Google Scholar]
76. Nirodi C, Hart J, Dhawan P, Moon NS, Nepveu A, Richmond AThe role of CDP in the negative regulation of CXCL1 gene expression. J Biol Chem. 2001;276:26122–26131.[Google Scholar]
77. Blochlinger K, Bodmer R, Jack J, Jan LY, Jan YNPrimary structure and expression of a product from cut, a locus involved in specifying sensory organ identity in Drosophila. Nature. 1988;333:629–635.[PubMed][Google Scholar]
78. Neufeld EJ, Skalnik DG, Lievens PM, Orkin SHHuman CCAAT displacement protein is homologous to the Drosophila homeoprotein, cut. Nat Genet. 1992;1:50–55.[PubMed][Google Scholar]
79. Luo W, Skalnik DGInterferon regulatory factor-2 directs transcription from the gp91phox promoter. J Biol Chem. 1996;271:18203–18210.[PubMed][Google Scholar]
80. Coqueret O, Berube G, Nepveu AThe mammalian cut homeodomain protein functions as a cell-cycle-dependent transcriptional repressor which downmodulates p21WAF1/CIP1/SDI1 in S phase. EMBO J. 1998;17:4680–4694.[Google Scholar]
81. Van Gurp MF, Pratap J, Luong M, Javed A, Hoffmann H, Giordano A, Stein JL, Neufeld EJ, Lian JB, Stein GS, Van Wijnen AJThe CCAAT displacement protein/cut homeodomain protein represses osteocalcin gene transcription and forms complexes with the retinoblastoma protein-related protein p107 and cyclin A. Cancer Res. 1999;59:5980–5988.[PubMed][Google Scholar]
82. Kim EC, Lau JS, Rawlings S, Lee ASPositive and negative regulation of the human thymidine kinase promoter mediated by CCAAT binding transcription factors NF-Y/CBF, dbpA, and CDP/cut. Cell Growth Differ. 1997;8:1329–1338.[PubMed][Google Scholar]
83. Miller H, Asselin C, Dufort D, Yang JQ, Gupta K, Marcu KB, Nepveu AA cis-acting element in the promoter region of the murine c-myc gene is necessary for transcriptional block. Mol Cell Biol. 1989;9:5340–5349.[Google Scholar]
84. Vanden Berghe W, De Bosscher K, Boone E, Plaisance S, Haegeman GThe nuclear factor-kappaB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter. J Biol Chem. 1999;274:32091–32098.[PubMed][Google Scholar]
85. Li S, Aufiero B, Schiltz RL, Walsh MJRegulation of the homeodomain CCAAT displacement/cut protein function by histone acetyltransferases p300/CREB-binding protein (CBP)-associated factor and CBP. Proc Natl Acad Sci USA. 2000;97:7166–7171.[Google Scholar]
86. Li S, Moy L, Pittman N, Shue G, Aufiero B, Neufeld EJ, LeLeiko NS, Walsh MJTranscriptional repression of the cystic fibrosis transmembrane conductance regulator gene, mediated by CCAAT displacement protein/cut homolog, is associated with histone deacetylation. J Biol Chem. 1999;274:7803–7815.[PubMed][Google Scholar]
87. Shattuck-Brandt RL, Richmond AEnhanced degradation of I-kappaB alpha contributes to endogenous activation of NF-kappaB in Hs294T melanoma cells. Cancer Res. 1997;57:3032–3039.[PubMed][Google Scholar]
88. Yang J, Richmond AConstitutive IkappaB kinase activity correlates with nuclear factor-kappaB activation in human melanoma cells. Cancer Res. 2001;61:4901–4909.[PubMed][Google Scholar]
89. Nasuhara Y, Adcock IM, Catley M, Barnes PJ. Differential IkappaB kinase activation and IkappaBalpha degradation by interleukin-1beta and tumor necrosis factor-alpha in human U937 monocytic cells. Evidence for additional regulatory steps in kappaB-dependent transcription. J Biol Chem. 1999;274:19965–19972.[PubMed]
90. Takaori-Kondo A, Hori T, Fukunaga K, Morita R, Kawamata S, Uchiyama TBoth amino- and carboxyl-terminal domains of TRAF3 negatively regulate NF-kappaB activation induced by OX40 signaling. Biochem Biophys Res Commun. 2000;272:856–863.[PubMed][Google Scholar]
91. Delhase M, Hayakawa M, Chen Y, Karin MPositive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science. 1999;284:309–313.[PubMed][Google Scholar]
92. Matsushima A, Kaisho T, Rennert PD, Nakano H, Kurosawa K, Uchida D, Takeda K, Akira S, Matsumoto MEssential role of nuclear factor (NF)-kappaB-inducing kinase and inhibitor of kappaB (IkappaB) kinase alpha in NF-kappaB activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I. J Exp Med. 2001;193:631–636.[Google Scholar]
93. Lazar-Molnar E, Hegyesi H, Toth S, Falus AAutocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine. 2000;12:547–554.[PubMed][Google Scholar]
94. Crespo P, Leon JRas proteins in the control of the cell cycle and cell differentiation. Cell Mol Life Sci. 2000;57:1613–1636.[PubMed][Google Scholar]
95. Mangues R, Seidman I, Gordon JW, Pellicer AOverexpression of the N-ras proto-oncogene, not somatic mutational activation, associated with malignant tumors in transgenic mice. Oncogene. 1992;7:2073–2076.[PubMed][Google Scholar]
96. Matsumoto K, Asano T, Endo TNovel small GTPase M-Ras participates in reorganization of actin cytoskeleton. Oncogene. 1997;15:2409–2417.[PubMed][Google Scholar]
97. Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi CM-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. J Biol Chem. 1999;274:23850–23857.[PubMed][Google Scholar]
98. Lopez-Ilasaca M, Crespo P, Pellici PG, Gutkind JS, Wetzker RLinkage of G protein-coupled receptors to the MAPK signaling pathway through PI 3-kinase gamma. Science. 1997;275:394–397.[PubMed][Google Scholar]
99. Wang D, Yang W, Du J, Devalaraja MN, Liang P, Matsumoto K, Tsubakimoto K, Endo T, Richmond AMGSA/GRO-mediated melanocyte transformation involves induction of Ras expression. Oncogene. 2000;19:4647–4659.[Google Scholar]
100. Bours V, Bentires-Alj M, Hellin AC, Viatour P, Robe P, Delhalle S, Benoit V, Merville MPNuclear factor-kappa B, cancer, and apoptosis. Biochem Pharmacol. 2000;60:1085–1089.[PubMed][Google Scholar]
101. Bellacosa A, Franke TF, Gonzalez-Portal ME, Datta K, Taguchi T, Gardner J, Cheng JQ, Testa JR, Tsichlis PNStructure, expression and chromosomal mapping of c-akt: relationship to v-akt and its implications. Oncogene. 1993;8:745–754.[PubMed][Google Scholar]
102. Coffer PJ, Jin J, Woodgett JRProtein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J. 1998;335:1–13.[Google Scholar]
103. Toker A, Newton ACCellular signaling: pivoting around PDK-1. Cell. 2000;103:185–188.[PubMed][Google Scholar]
104. Meier R, Hemmings BARegulation of protein kinase. Recept Signal Transduct Res. 1999;19:121–128.[PubMed][Google Scholar]
105. Datta SR, Brunet A, Greenberg MECellular survival: a play in three Akts. Genes Dev. 1999;13:2905–2927.[PubMed][Google Scholar]
106. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DBNF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 1999;401:82–85.[PubMed][Google Scholar]
107. Romashkova JA, Makarov SSNF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 1999;401:86–90.[PubMed][Google Scholar]
108. Madrid LV, Wang CY, Guttridge DC, Schottelius AJ, Baldwin AS, Jr, Mayo MWAkt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappaB. Mol Cell Biol. 2000;20:1626–1638.[Google Scholar]
109. Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R, Tonks NKP-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci USA. 1997;94:9052–9057.[Google Scholar]
110. Li J, Simpson L, Takahashi M, Miliaresis C, Myers MP, Tonks N, Parsons RThe PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. Cancer Res. 1998;58:5667–5672.[PubMed][Google Scholar]
111. Guldberg P, thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen JDisruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res. 1997;57:3660–3663.[PubMed][Google Scholar]
112. Xiong Y, Zhang H, Beach DSubunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev. 1993;7:1572–1583.[PubMed][Google Scholar]
113. Sherr CJ, Roberts JMCDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–1512.[PubMed][Google Scholar]
114. Serrano M, Gomez-Lahoz E, DePinho RA, Beach D, Bar-Sagi DInhibition of ras-induced proliferation and cellular transformation by p16INK4. Science. 1995;267:249–252.[PubMed][Google Scholar]
115. Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M, Peters G, Bartek JRetinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature. 1995;375:503–506.[PubMed][Google Scholar]
116. Sherr CJTumor surveillance via the ARF-p53 pathway. Genes Dev. 1998;12:2984–2991.[PubMed][Google Scholar]
117. Yang J, Luan J, Yu Y, Li C, DePinho RA, Chin L, Richmond AInduction of melanoma in murine macrophage inflammatory protein 2 transgenic mice heterozygous for inhibitor of kinase/alternate reading frame. Cancer Res. 2001;61:8150–8157.[PubMed][Google Scholar]
118. Elliott PJ, Ross JSThe proteasome: a new target for novel drug therapies. Am J Clin Pathol. 2001;116:637–646.[PubMed][Google Scholar]
119. May MJ, D’Acquisto F, Madge LA, Glockner J, Pober JS, Ghosh SSelective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science. 2000;289:1550–1554.[PubMed][Google Scholar]