Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor View Full Text


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Article Info

DATE

2013-03-04

AUTHORS

T M Becker, S C Boyd, B Mijatov, K Gowrishankar, S Snoyman, G M Pupo, R A Scolyer, G J Mann, R F Kefford, X D Zhang, H Rizos

ABSTRACT

Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAFV600E is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAFV600E signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B-RAFV600E activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of STAT3 activity disrupted B-RAFV600E-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that STAT3 has a central role in the survival and contributes to chemoresistance of B-RAFV600E melanoma. More... »

PAGES

1158-1166

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/onc.2013.45

    DOI

    http://dx.doi.org/10.1038/onc.2013.45

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1002813670

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/23455323


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