KEGG   PATHWAY: mmu05218
mmu05218                    Pathway                                

Melanoma - Mus musculus (mouse)
Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. Melanoma arises from the malignant transformation of pigment-producing cells, melanocytes. The only known environmental risk factor is exposure to ultraviolet (UV) light and in people with fair skin the risk is greatly increased. Melanoma pathogenesis is also driven by genetic factors. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Melanoma development has been shown to be strongly associated with inactivation of the p16INK4a/cyclin dependent kinases 4 and 6/retinoblastoma protein (p16INK4a/CDK4,6/pRb) and p14ARF/human double minute 2/p53 (p14ARF/HMD2/p53) tumor suppressor pathways. MITF and TP53 are implicated in further melanoma progression.
Human Diseases; Cancer: specific types
Pathway map
mmu05218  Melanoma

Mus musculus (mouse) [GN:mmu]
14164  Fgf1; fibroblast growth factor 1 [KO:K18496]
14173  Fgf2; fibroblast growth factor 2 [KO:K18497]
14174  Fgf3; fibroblast growth factor 3 [KO:K04358]
14175  Fgf4; fibroblast growth factor 4 [KO:K04358]
14176  Fgf5; fibroblast growth factor 5 [KO:K04358]
14178  Fgf7; fibroblast growth factor 7 [KO:K04358]
14179  Fgf8; fibroblast growth factor 8 [KO:K04358]
14180  Fgf9; fibroblast growth factor 9 [KO:K04358]
14165  Fgf10; fibroblast growth factor 10 [KO:K04358]
80903  Fgf16; fibroblast growth factor 16 [KO:K04358]
14171  Fgf17; fibroblast growth factor 17 [KO:K04358]
14172  Fgf18; fibroblast growth factor 18 [KO:K04358]
80857  Fgf20; fibroblast growth factor 20 [KO:K04358]
67112  Fgf22; fibroblast growth factor 22 [KO:K04358]
14177  Fgf6; fibroblast growth factor 6 [KO:K04358]
14170  Fgf15; fibroblast growth factor 15 [KO:K22603]
56636  Fgf21; fibroblast growth factor 21 [KO:K22429]
64654  Fgf23; fibroblast growth factor 23 [KO:K22428]
15234  Hgf; hepatocyte growth factor [KO:K05460]
16000  Igf1; insulin-like growth factor 1 [KO:K05459]
18590  Pdgfa; platelet derived growth factor, alpha [KO:K04359]
18591  Pdgfb; platelet derived growth factor, B polypeptide [KO:K17386]
54635  Pdgfc; platelet-derived growth factor, C polypeptide [KO:K05450]
71785  Pdgfd; platelet-derived growth factor, D polypeptide [KO:K05450]
13645  Egf; epidermal growth factor [KO:K04357]
14182  Fgfr1; fibroblast growth factor receptor 1 [KO:K04362] [EC:]
17295  Met; met proto-oncogene [KO:K05099] [EC:]
16001  Igf1r; insulin-like growth factor I receptor [KO:K05087] [EC:]
18595  Pdgfra; platelet derived growth factor receptor, alpha polypeptide [KO:K04363] [EC:]
18596  Pdgfrb; platelet derived growth factor receptor, beta polypeptide [KO:K05089] [EC:]
13649  Egfr; epidermal growth factor receptor [KO:K04361] [EC:]
15461  Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
16653  Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
18176  Nras; neuroblastoma ras oncogene [KO:K07828]
11836  Araf; Araf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:]
109880  Braf; Braf transforming gene [KO:K04365] [EC:]
110157  Raf1; v-raf-leukemia viral oncogene 1 [KO:K04366] [EC:]
26395  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
26396  Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
26417  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
12443  Ccnd1; cyclin D1 [KO:K04503]
12567  Cdk4; cyclin-dependent kinase 4 [KO:K02089] [EC:]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
11651  Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:]
11652  Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:]
23797  Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:]
12015  Bad; BCL2-associated agonist of cell death [KO:K02158]
19211  Pten; phosphatase and tensin homolog [KO:K01110] [EC:]
12578  Cdkn2a; cyclin dependent kinase inhibitor 2A [KO:K06621]
17246  Mdm2; transformed mouse 3T3 cell double minute 2 [KO:K06643] [EC:]
22059  Trp53; transformation related protein 53 [KO:K04451]
12575  Cdkn1a; cyclin-dependent kinase inhibitor 1A (P21) [KO:K06625]
12571  Cdk6; cyclin-dependent kinase 6 [KO:K02091] [EC:]
19645  Rb1; RB transcriptional corepressor 1 [KO:K06618]
13555  E2f1; E2F transcription factor 1 [KO:K17454]
242705  E2f2; E2F transcription factor 2 [KO:K09389]
13557  E2f3; E2F transcription factor 3 [KO:K06620]
12550  Cdh1; cadherin 1 [KO:K05689]
13197  Gadd45a; growth arrest and DNA-damage-inducible 45 alpha [KO:K04402]
17873  Gadd45b; growth arrest and DNA-damage-inducible 45 beta [KO:K04402]
23882  Gadd45g; growth arrest and DNA-damage-inducible 45 gamma [KO:K04402]
12028  Bax; BCL2-associated X protein [KO:K02159]
12018  Bak1; BCL2-antagonist/killer 1 [KO:K14021]
107986  Ddb2; damage specific DNA binding protein 2 [KO:K10140]
27015  Polk; polymerase (DNA directed), kappa [KO:K03511] [EC:]
17342  Mitf; melanogenesis associated transcription factor [KO:K09455]
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Miller AJ, Mihm MC Jr.
N Engl J Med 355:51-65 (2006)
Chin L.
The genetics of malignant melanoma: lessons from mouse and man.
Nat Rev Cancer 3:559-70 (2003)
Takata M, Saida T.
Genetic alterations in melanocytic tumors.
J Dermatol Sci 43:1-10 (2006)
Chudnovsky Y, Khavari PA, Adams AE.
Melanoma genetics and the development of rational therapeutics.
J Clin Invest 115:813-24 (2005)
Merlino G.
Cancer biology: the weakest link?
Nature 436:33-5 (2005)
Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE, Sellers WR.
Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.
Nature 436:117-22 (2005)
Levy C, Khaled M, Fisher DE.
MITF: master regulator of melanocyte development and melanoma oncogene.
Trends Mol Med 12:406-14 (2006)
Tsao H, Goel V, Wu H, Yang G, Haluska FG.
Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma.
J Invest Dermatol 122:337-41 (2004)
Gruss C, Herlyn M.
Role of cadherins and matrixins in melanoma.
Curr Opin Oncol 13:117-23 (2001)
Thompson JF, Scolyer RA, Kefford RF.
Cutaneous melanoma.
Lancet 365:687-701 (2005)
Omholt K, Platz A, Kanter L, Ringborg U, Hansson J.
NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression.
Clin Cancer Res 9:6483-8 (2003)
Hussein MR.
The TP53 tumor suppressor gene and melanoma tumorigenesis: is there a relationship?
Tumour Biol 25:200-7 (2004)
Lazar-Molnar E, Hegyesi H, Toth S, Falus A.
Autocrine and paracrine regulation by cytokines and growth factors in melanoma.
Cytokine 12:547-54 (2000)
mmu04010  MAPK signaling pathway
mmu04110  Cell cycle
mmu04115  p53 signaling pathway
mmu04151  PI3K-Akt signaling pathway
mmu04520  Adherens junction
mmu04916  Melanogenesis
KO pathway

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