title: Proliferation arrest in B-Raf mutant melanoma cell lines upon MAPK pathway activation.
abstract: Due to elaborate control mechanisms, in benign tumors the activation of oncogenes primarily induces senescence, associated with cessation of cellular proliferation; for example, melanocytic nevi expressing mutant B-Raf. These mechanisms include the RB and/or the p53 pathway. The current model of melanomagenesis postulates that progression to immortal melanoma cells requires inactivating aberrations in signaling cascades controlling senescence. Thus, melanoma cells carrying mutant B-Raf should be resistant to mitogen-activated protein kinase (MAPK) pathway-induced senescence. Here, we demonstrate that hyperactivation of the MAPK pathway following activation of an inducible form of oncogenic C-Raf induces a senescence-like proliferation arrest in B-Raf mutant melanoma cells. This Raf-induced senescence is initially strictly dependent on MEK signaling, but seems to be independent of MAPK signaling after prolonged continuance. It is associated with reduced levels of RB phosphorylation and an increase in p21 expression, but is independent of p16(Ink4a) and p53. These data argue against the existence of fundamental changes in melanoma cells completely precluding senescence.
authors.affiliation: Klinik für Dermatologie, Venerologie und Allergologie, Julius-Maximilians-Universität Joseph-Schneider Str. 2, Würzburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Houben
authors.forename: Sonja
authors.initials: S
authors.lastname: Ortmann
authors.forename: Astrid
authors.initials: A
authors.lastname: Drasche
authors.forename: Jakob
authors.initials: J
authors.lastname: Troppmair
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Becker
mesh_terms: D000818:Animals; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014161:Transduction, Genetic
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D016160:Retinoblastoma Protein; D013629:Tamoxifen; C016601:afimoxifene; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases