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c-Kit mutants require hypoxia-inducible factor 1α to transform melanocytes

Oncogene volume 29, pages 227–236 (2010)Cite this article

Abstract

Many studies have highlighted the critical role of c-Kit in normal melanocyte development but its role in melanoma development remains unclear. Although c-Kit expression is often lost during melanoma progression, a subset of melanoma has been found to overexpress c-Kit and mutations activating c-Kit have recently been identified in some acral and mucosal melanoma. To address the role of these c-Kit mutants in the transformation of melanocytes, we characterized the physiological responses of melanocytes expressing the most frequent c-Kit mutants found in melanoma (K642E and L576P) and a novel mutant we identified in an acral melanoma. We analysed signaling pathways activated downstream of c-Kit and showed that all three mutants led to a strong activation of the phosphatidyl-inositol-3 kinase (PI3K) pathway but only weak activation of the Ras/Raf/Mek/Erk pathway, which was not sufficient to promote uncontrolled melanocyte proliferation and transformation. However, in hypoxic conditions or coexpressed with a constitutively active form of hypoxia-inducible factor 1α (HIF-1α), c-Kit mutants activate the Ras/Raf/Mek/Erk pathway, stimulate proliferation and transform melanocytes. Proliferation of melanocytes transformed by these mutants was specifically inhibited by imatinib. These results show for the first time that melanocytes require a specific epigenetic environment to be transformed by c-Kit mutants and highlight a distinct molecular mechanism of melanocyte transformation.

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Acknowledgements

We thank Professor Richard Marais for 501mel cells and pMCEF vector, Dr Lars Rönnstrand for a wild-type c-Kit expression vector and Dr Frank Bunn for the vector expressing HIF-1α (401Δ603). This work was funded by INSERM, Université Paris XII, Société Française de Dermatologie, Ligue Contre le Cancer (Comité du Val de Marne) and Institut National du Cancer.

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Authors and Affiliations

  1. INSERM U976, Hôpital Saint Louis, Paris, France

    G Monsel, N Ortonne, M Bagot, A Bensussan & N Dumaz

  2. Department of Pathology, AP-HP, Groupe Hospitalier Henri Mondor-Albert Chenevier, Créteil, France

    N Ortonne

  3. Department of Dermatology, AP-HP, Groupe Hospitalier Henri Mondor-Albert Chenevier, Créteil, France

    M Bagot & A Bensussan

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  1. G Monsel
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  2. N Ortonne
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Correspondence to N Dumaz.

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Monsel, G., Ortonne, N., Bagot, M. et al. c-Kit mutants require hypoxia-inducible factor 1α to transform melanocytes. Oncogene 29, 227–236 (2010). https://doi.org/10.1038/onc.2009.320

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