title: Malignant transformation of melanocytes to melanoma by constitutive activation of mitogen-activated protein kinase kinase (MAPKK) signaling.
abstract: Malignant melanoma is the cancer with the most rapid increase in incidence in the United States. Ultraviolet light and deficiency of the p16ink4a gene are known factors that predispose one to the development of malignant melanoma. The signal transduction pathways that underlie the progression of melanoma from their precursors, atypical nevi, are not well understood. We examined activation of the MAP kinase pathway in atypical nevi and melanoma cells and found that this pathway is activated in melanomas. To determine the functional significance of this activation, we introduced constitutively active MAP kinase kinase (MAPKK) into immortalized melanocytes. The introduction of this gene into melanocytes leads to tumorigenesis in nude mice, activation of the angiogenic switch, and increased production of the proangiogenic factor, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs). Activation of MAP kinase signaling may be an important pathway involved in melanoma transformation. Inhibition of MAP kinase signaling may be useful in the prevention and treatment of melanoma.
authors.affiliation: Department of Dermatology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Baskaran
authors.initials: B
authors.lastname: Govindarajan
authors.forename: Xianhe
authors.initials: X
authors.lastname: Bai
authors.forename: Cynthia
authors.initials: C
authors.lastname: Cohen
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.forename: Susan
authors.initials: S
authors.lastname: Kilroy
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Louis
authors.forename: Marsha
authors.initials: M
authors.lastname: Moses
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D016228:Endothelial Growth Factors / Q000378:metabolism; D004789:Enzyme Activation; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology* / Q000473:pathology*; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020929:Mitogen-Activated Protein Kinase Kinases; D020782:Matrix Metalloproteinases