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    Constitutive Rac Activation Is Not Sufficient to Initiate Melanocyte Neoplasia but Accelerates Malignant Progression.

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    Authors
    Dalton, Lucy E
    Kamarashev, J
    Ramirez, I
    White, Gavin R M
    Malliri, Angeliki
    Hurlstone, A
    Affiliation
    Cancer Research UK Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
    Issue Date
    2013-01-21
    
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    Abstract
    Deregulated Ras signaling initiates and maintains melanocyte neoplasia. The Rho-like GTPase Rac has been implicated in Ras-induced neoplastic transformation. Moreover, a recurrent UV-induced mutation activating RAC1 has recently been detected in human melanoma. Here, a role for Rac in melanoma initiation and progression was investigated in human melanomas and zebrafish models of melanocyte neoplasia. Immunohistochemical analysis revealed RAC expression and activity restricted to melanocytes at the junction of the epidermis and dermis in benign neoplasms. Malignant melanocytes displayed elevated RAC activity that extended into the suprabasal epidermis, deeper into the dermis, and was maintained in metastases. Previously, we have used zebrafish transgenic models to demonstrate that deregulated Ras/Raf/mitogen-activated protein kinase signaling can initiate melanocyte neoplasia. Expression of a constitutively active RAC1 mutant (V12RAC1) was not sufficient to initiate melanocyte neoplasia in this organism. Furthermore, we did not detect an additive effect when combined with V600EBRAF, nor could V12RAC1 substitute for suppressed Pi3k signaling to restore melanoma progression. However, coexpression of V12RAC1 and oncogenic RAS accelerated tumor nodule formation. Immunohistochemical analysis revealed that the Rac activator Tiam1 (T-cell lymphoma invasion and metastasis 1) is overexpressed in melanoma tumor nodules in both zebrafish and humans. Thus, our data suggest that Rac contributes to the progression of melanoma and that Tiam1 may activate Rac in nodular presentations.Journal of Investigative Dermatology advance online publication, 21 February 2013; doi:10.1038/jid.2013.23.
    Citation
    Constitutive Rac Activation Is Not Sufficient to Initiate Melanocyte Neoplasia but Accelerates Malignant Progression. 2013: J Invest Dermatol
    Journal
    Journal of Investigative Dermatology
    URI
    http://hdl.handle.net/10541/273023
    DOI
    10.1038/jid.2013.23
    PubMed ID
    23337888
    Type
    Article
    Language
    en
    ISSN
    1523-1747
    ae974a485f413a2113503eed53cd6c53
    10.1038/jid.2013.23
    Scopus Count
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    All Paterson Institute for Cancer Research

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