title: Phosphorylation of BRN2 modulates its interaction with the Pax3 promoter to control melanocyte migration and proliferation.
abstract: MITF-M and PAX3 are proteins central to the establishment and transformation of the melanocyte lineage. They control various cellular mechanisms, including migration and proliferation. BRN2 is a POU domain transcription factor expressed in melanoma cell lines and is involved in proliferation and invasion, at least in part by regulating the expression of MITF-M and PAX3. The T361 and S362 residues of BRN2, both in the POU domain, are conserved throughout the POU protein family and are targets for phosphorylation, but their roles in vivo remain unknown. To examine the role of this phosphorylation, we generated mutant BRN2 in which these two residues were replaced with alanines (BRN2TS→BRN2AA). When expressed in melanocytes in vitro or in the melanocyte lineage in transgenic mice, BRN2TS induced proliferation and repressed migration, whereas BRN2AA repressed both proliferation and migration. BRN2TS and BRN2AA bound and repressed the MITF-M promoter, whereas PAX3 transcription was induced by BRN2TS but repressed by BRN2AA. Expression of the BRN2AA transgene in a Mitf heterozygous background and in a Pax3 mutant background enhanced the coat color phenotype. Our findings show that melanocyte migration and proliferation are controlled both through the regulation of PAX3 by nonphosphorylated BRN2 and through the regulation of MITF-M by the overall BRN2 level.
authors.affiliation: Institut Curie, Developmental Genetics of Melanocytes, Orsay, France.
authors.forename: Irina
authors.initials: I
authors.lastname: Berlin
authors.forename: Laurence
authors.initials: L
authors.lastname: Denat
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Steunou
authors.forename: Isabel
authors.initials: I
authors.lastname: Puig
authors.forename: Delphine
authors.initials: D
authors.lastname: Champeval
authors.forename: Sophie
authors.initials: S
authors.lastname: Colombo
authors.forename: Karen
authors.initials: K
authors.lastname: Roberts
authors.forename: Elise
authors.initials: E
authors.lastname: Bonvin
authors.forename: Yveline
authors.initials: Y
authors.lastname: Bourgeois
authors.forename: Irwin
authors.initials: I
authors.lastname: Davidson
authors.forename: Véronique
authors.initials: V
authors.lastname: Delmas
authors.forename: Laurence
authors.initials: L
authors.lastname: Nieto
authors.forename: Colin R
authors.initials: CR
authors.lastname: Goding
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000072041:PAX3 Transcription Factor; D050809:POU Domain Factors / Q000235:genetics / Q000378:metabolism*; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010641:Phenotype; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D009419:Nerve Tissue Proteins; D000072041:PAX3 Transcription Factor; D050809:POU Domain Factors; D051761:Paired Box Transcription Factors; C068686:Pax3 protein, mouse; C074066:Pou3f2 protein, mouse