title: ERK-regulated differential expression of the Mitf 6a/b splicing isoforms in melanoma.
abstract: The master regulator of the melanocyte lineage Mitf is intimately involved in development as well as melanoma, controlling cell survival, differentiation, proliferation and metastasis/migration. Consistent with its central role, Mitf expression and Mitf post-translational modifications are tightly regulated. An additional potential level of regulation is afforded by differential splicing of Mitf exon-6 leading to the generation of two isoforms that differ by the presence of six amino-acids in the Mitf (+) isoform and which have differential effects on cell cycle progression. However, whether the ratio of the two isoforms is regulated and whether their expression correlates with melanoma progression is not known. Here, we show that the differential expression of the Mitf 6a/b isoforms is dependent on the MAPKinase signalling, being linked to the activation of MEK1-ERK2, but not to N-RAS/B-RAF mutation status. In addition, quantification of Mitf 6a/b splicing forms in 86 melanoma samples revealed substantially increased levels of the Mitf (-) form in a subset of metastatic melanomas. The results suggest that differential expression of the Mitf 6a/b isoforms may represent an additional mechanism for regulating Mitf function and melanoma biology.
authors.affiliation: CNRS-UMR6061, RTO-Team/Rennes-1 University, Rennes, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Primot
authors.forename: Ariane
authors.initials: A
authors.lastname: Mogha
authors.forename: Sébastien
authors.initials: S
authors.lastname: Corre
authors.forename: Karen
authors.initials: K
authors.lastname: Roberts
authors.forename: Julien
authors.initials: J
authors.lastname: Debbache
authors.forename: Henri
authors.initials: H
authors.lastname: Adamski
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dreno
authors.forename: Amir
authors.initials: A
authors.lastname: Khammari
authors.forename: Thierry
authors.initials: T
authors.lastname: Lesimple
authors.forename: Agnes
authors.initials: A
authors.lastname: Mereau
authors.forename: Colin R
authors.initials: CR
authors.lastname: Goding
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Galibert
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: C497234:MITF protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D020033:Protein Isoforms; D048049:Extracellular Signal-Regulated MAP Kinases