title: Oncogenic BRAF signalling increases Mcl-1 expression in cutaneous metastatic melanoma.
abstract: The Bcl-2 family member Mcl-1 is essential for melanoma survival; however, the influence of oncogenic BRAF signalling remains elusive. In this study, Mcl-1 splice variant expression was determined in a panel of melanoma cell lines in relation to BRAF mutational status. Mcl-1L mRNA expression was increased in melanoma cells compared with primary melanocytes with significantly increased mRNA and protein expression observed in BRAF(V600E) mutant melanoma cells. Although no change in Mcl-1S mRNA was observed, Mcl-1S protein expression also increased in BRAF mutant melanoma cells. Additionally, while over-expression of mutant BRAF(V600E) increased both Mcl-1L and Mcl-1S expression, inhibition of hyperactive BRAF signalling resulted in decreased Mcl-1L expression. These studies suggest that the regulation of Mcl-1 expression by BRAF signalling is increased by oncogenic activation of BRAF, revealing a mechanism of apoptotic resistance which may be overcome by the use of more specifically targeted Mcl-1 inhibitors.
authors.affiliation: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: McKee
authors.forename: David S
authors.initials: DS
authors.lastname: Hill
authors.forename: Christopher P F
authors.initials: CP
authors.lastname: Redfern
authors.forename: Jane L
authors.initials: JL
authors.lastname: Armstrong
authors.forename: Penny E
authors.initials: PE
authors.lastname: Lovat
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D000096142:Cutaneous Malignant Melanoma
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Bcl-2 proteins; Mcl-1 splice variant expression; melanoma; oncogenic BRAF signalling