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Dissection of RAS downstream pathways in melanomagenesis: a role for Ral in transformation

Oncogene volume 29, pages 2449–2456 (2010)Cite this article

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A Corrigendum to this article was published on 14 April 2011

Abstract

Cutaneous malignant melanoma is considered one of the most deadly human cancers, based on both its penchant for metastatic spread and its typical resistance to currently available therapy. Long known to harbor oncogenic NRAS mutations, melanomas were more recently reported to be frequent bearers of activating mutations in BRAF, one of the effectors situated downstream of wild-type NRAS. NRAS and BRAF mutations are rarely found in the same melanoma, suggesting that they may possess important overlapping oncogenic activities. Here, we compare and contrast the oncogenic roles of the three major NRas downstream effectors, Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine exchange factor (RalGEF), using genetically engineered Arf-deficient immortalized mouse melanocytes as a model system. Although no single downstream pathway could recapitulate all of the consequences of oncogenic NRas expression, our data indicate a prominent role for BRaf and PI3K in melanocyte senescence and invasiveness, respectively. More surprisingly, we discovered that constitutive RalGEF activation had a major impact on several malignant phenotypes, particularly anchorage-independent growth, indicating that this often overlooked pathway should be more carefully evaluated as a possible therapeutic target.

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Acknowledgements

We thank Dr Christopher Counter (Duke University) for useful discussions, and for communicating data before publication. We acknowledge Dr Paul Khavari (Stanford University) for gifting the NRas, PI3K and BRaf retroviral vectors, and Drs Frederique Zindy and Charles Sherr (St Jude Children's Research Hospital) for the Arf-deficient mouse skins from which the immortalized melanocytes were generated. The PEP7 and PEP8H antibodies were a gift from Dr Vince Hearing (NCI). The pEF-CAAX-Raf-1 vector was a gift from Dr Silvio J Gutkind (NIH/NIDCR). This work was supported in part by the Intramural Research Program of the NCI, National Institutes of Health, in part by NCI Contract N01-CO-12400, and in part by Wellcome Trust Program Grant 078327 (to EVS).

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Author notes

  1. P J Mishra, L Ha and J Rieker: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA

    P J Mishra, L Ha, J Rieker & G Merlino

  2. Division of Monoclonal Antibody, Center of Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA

    L Ha

  3. Division of Basic Medical Sciences, St George's, University of London, London, UK

    E V Sviderskaya & D C Bennett

  4. Cell and Cancer Biology Branch, National Cancer Institute, NIH, Bethesda, MD, USA

    M D Oberst & K Kelly

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  1. P J Mishra
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Correspondence to G Merlino.

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Mishra, P., Ha, L., Rieker, J. et al. Dissection of RAS downstream pathways in melanomagenesis: a role for Ral in transformation. Oncogene 29, 2449–2456 (2010). https://doi.org/10.1038/onc.2009.521

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