- Title
- Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor
- Creator
- Becker, T. M.; Boyd, S. C.; Rizos, H.; Mijatov, B.; Gowrishankar, K.; Snoyman, S.; Pupo, G. M.; Scolyer, R. A.; Mann, G. J.; Kefford, R. F.; Zhang, X. D.
- Relation
- NHMRC.633004
- Relation
- Oncogene Vol. 33, Issue 9, p. 1158-1166
- Publisher Link
- http://dx.doi.org/10.1038/onc.2013.45
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2014
- Description
- 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.
- Subject
- MAPK; B-RAF; STAT3; Mcl-1; anoikis
- Identifier
- http://hdl.handle.net/1959.13/1064080
- Identifier
- uon:17459
- Identifier
- ISSN:0950-9232
- Language
- eng
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