title: BPTF transduces MITF-driven prosurvival signals in melanoma cells.
abstract: Microphthalmia-associated transcription factor (MITF) plays a critical and complex role in melanocyte transformation. Although several downstream targets of MITF action have been identified, the precise mechanisms by which MITF promotes melanocytic tumor progression are incompletely understood. Recent studies identified an oncogenic role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression, in part through activation of BCL2, a canonical target of MITF signaling. Analysis of the BPTF promoter identified a putative MITF-binding site, suggesting that MITF may regulate BPTF expression. Overexpression of MITF resulted in up-regulation of BPTF in a panel of melanoma and melanocyte cell lines. shRNA-mediated down-regulation of MITF in melanoma cells was accompanied by down-regulation of BPTF and BPTF-regulated genes (including BCL2) and resulted in reduced proliferative capacity of melanoma cells. The suppression of cell growth mediated by MITF silencing was rescued by overexpression of BPTF cDNA. Binding of MITF to the BPTF promoter was demonstrated using ChIP analysis. MITF overexpression resulted in direct transcriptional activation of BPTF, as evidenced by increased luciferase activity driven by the BPTF promoter. These results indicate that BPTF transduces key prosurvival signals driven by MITF, further supporting its important role in promoting melanoma cell survival and progression.
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, CA 94107;
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Dar
authors.affiliation: Department of Urology, Veterans Affairs Medical Center, University of California, San Francisco, CA 94121;
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, CA 94107;
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bezrookove
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, CA 94107;
authors.forename: Binh
authors.initials: B
authors.lastname: Phan
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, CA 94107;
authors.forename: Sarah
authors.initials: S
authors.lastname: Ursu
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, CA 94107;
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nosrati
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, CA 94107;
authors.forename: David
authors.initials: D
authors.lastname: De Semir
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, CA 94107;
authors.forename: Richard W
authors.initials: RW
authors.lastname: Sagebiel
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, CA 94107;
authors.forename: James R
authors.initials: JR
authors.lastname: Miller
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, CA 94107;
authors.forename: Robert
authors.initials: R
authors.lastname: Debs
authors.affiliation: Department of Dermatology and Pharmaceutical Chemistry, University of California, San Francisco, CA 94143 JCleaver@cc.ucsf.edu kashani@cpmcri.org.
authors.forename: James E
authors.initials: JE
authors.lastname: Cleaver
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, CA 94107; JCleaver@cc.ucsf.edu kashani@cpmcri.org.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kashani-Sabet
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001665:Binding Sites; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000092468:Bromodomain Containing Proteins
chemical_list: D034961:Antigens, Nuclear; D008156:Luciferases; D051739:Microphthalmia-Associated Transcription Factor; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C497234:MITF protein, human; C406238:fetal Alzheimer antigen; D000092468:Bromodomain Containing Proteins
keywords: melanoma; oncogenes; signaling cascade