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      Activated Mutant NRas Q61K Drives Aberrant Melanocyte Signaling, Survival, and Invasiveness via a Rac1-Dependent Mechanism

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          Abstract

          Around a fifth of melanomas exhibit an activating mutation in the oncogene NRas that confers constitutive signaling to proliferation and promotes tumor initiation. NRas signals downstream of the major melanocyte tyrosine kinase receptor c-kit and activated NRas results in increased signaling via the extracellular signal–regulated kinase (ERK)/MAPK/ERK kinase/mitogen-activated protein kinase (MAPK) pathways to enhance proliferation. The Ras oncogene also activates signaling via the related Rho GTPase Rac1, which can mediate growth, survival, and motility signaling. We tested the effects of activated NRas Q61K on the proliferation, motility, and invasiveness of melanoblasts and melanocytes in the developing mouse and ex vivo explant culture as well as in a melanoma transplant model. We find an important role for Rac1 downstream of NRas Q61K in mediating dermal melanocyte survival in vivo in mouse, but surprisingly NRas Q61K does not appear to affect melanoblast motility or proliferation during mouse embryogenesis. We also show that genetic deletion or pharmacological inhibition of Rac1 in NRas Q61K induced melanoma suppresses tumor growth, lymph node spread, and tumor cell invasiveness, suggesting a potential value for Rac1 as a therapeutic target for activated NRas-driven tumor growth and invasiveness.

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          Most cited references35

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          Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation.

          C Marshall (1995)
          A number of different intracellular signaling pathways have been shown to be activated by receptor tyrosine kinases. These activation events include the phosphoinositide 3-kinase, 70 kDa S6 kinase, mitogen-activated protein kinase (MAPK), phospholipase C-gamma, and the Jak/STAT pathways. The precise role of each of these pathways in cell signaling remains to be resolved, but studies on the differentiation of mammalian PC12 cells in tissue culture and the genetics of cell fate determination in Drosophila and Caenorhabditis suggest that the extracellular signal-regulated kinase (ERK-regulated) MAPK pathway may be sufficient for these cellular responses. Experiments with PC12 cells also suggest that the duration of ERK activation is critical for cell signaling decisions.
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            RAS oncogenes: the first 30 years.

            From the pioneering work with acute transforming retroviruses to the current post-genomic era, RAS genes have always been at the leading edge of signal transduction and molecular oncology. Yet, a complete understanding of RAS function and dysfunction - mainly in human cancer - is still to come. The knowledge that has accumulated since their discovery 30 years ago has, however, been remarkable, and should pave the way for not only solving the outstanding issues regarding RAS biology, but also for developing efficacious drugs that could have a significant impact on cancer treatment.
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              Melanoma biology and new targeted therapy.

              Melanoma is a cancer that arises from melanocytes, specialized pigmented cells that are found predominantly in the skin. The incidence of melanoma is rising steadily in western populations--the number of cases worldwide has doubled in the past 20 years. In its early stages malignant melanoma can be cured by surgical resection, but once it has progressed to the metastatic stage it is extremely difficult to treat and does not respond to current therapies. Recent discoveries in cell signalling have provided greater understanding of the biology that underlies melanoma, and these advances are being exploited to provide targeted drugs and new therapeutic approaches.
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                Author and article information

                Journal
                J Invest Dermatol
                J. Invest. Dermatol
                The Journal of Investigative Dermatology
                Nature Publishing Group
                0022-202X
                1523-1747
                November 2012
                21 June 2012
                : 132
                : 11
                : 2610-2621
                Affiliations
                [1 ]The Beatson Institute for Cancer Research, Garscube Estate , Glasgow, UK
                [2 ]MRC Human Genetics Unit, Western General Hospital , Edinburgh, UK
                [3 ]Institut Curie, CNRS UMR3347 INSERM U1021, Institut Curie, Bat 110, Centre Universitaire , Orsay, France
                Author notes
                [* ]The Beatson Institute for Cancer Research , Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. E-mail: l.machesky@ 123456beatson.gla.ac.uk
                Article
                jid2012186
                10.1038/jid.2012.186
                3472562
                22718121
                6d139928-a8cc-4c46-8b87-aaf713828f81
                Copyright © 2012 The Society for Investigative Dermatology, Inc

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 29 February 2012
                : 20 April 2012
                : 20 April 2012
                Categories
                Original Article

                Dermatology
                Dermatology

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