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Houben, R; Ortmann, S; Drasche, A; Troppmair, J; Herold, MJ; Becker, JC.
Proliferation arrest in B-Raf mutant melanoma cell lines upon MAPK pathway activation.
J Invest Dermatol. 2009; 129(2):406-414 [OPEN ACCESS]
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Autor/innen der Med Uni Graz:
Becker Jürgen Christian
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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.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Cell Aging - physiology
Cell Division - physiology
Cell Line, Tumor -
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
Estrogen Antagonists - pharmacology
Extracellular Signal-Regulated MAP Kinases - metabolism
G1 Phase - physiology
Humans -
MAP Kinase Signaling System - drug effects MAP Kinase Signaling System - physiology
Melanoma - metabolism Melanoma - pathology Melanoma - physiopathology
Mice -
NIH 3T3 Cells -
Phosphorylation -
Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins B-raf - metabolism
Receptors, Estrogen - metabolism
Retinoblastoma Protein - metabolism
Skin Neoplasms - metabolism Skin Neoplasms - pathology Skin Neoplasms - physiopathology
Tamoxifen - analogs and derivatives Tamoxifen - pharmacology
Transduction, Genetic -

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