title: Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability.
abstract: Kit/SCF signaling and Mitf-dependent transcription are both essential for melanocyte development and pigmentation. To identify Mitf-dependent Kit transcriptional targets in primary melanocytes, microarray studies were undertaken. Among identified targets was BCL2, whose germline deletion produces melanocyte loss and which exhibited phenotypic synergy with Mitf in mice. BCL2's regulation by Mitf was verified in melanocytes and melanoma cells and by chromatin immunoprecipitation of the BCL2 promoter. Mitf also regulates BCL2 in osteoclasts, and both Mitf(mi/mi) and Bcl2(-/-) mice exhibit severe osteopetrosis. Disruption of Mitf in melanocytes or melanoma triggered profound apoptosis susceptible to rescue by BCL2 overexpression. Clinically, primary human melanoma expression microarrays revealed tight nearest neighbor linkage for MITF and BCL2. This linkage helps explain the vital roles of both Mitf and Bcl2 in the melanocyte lineage and the well-known treatment resistance of melanoma.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Gaël G
authors.initials: GG
authors.lastname: McGill
authors.forename: Martin
authors.initials: M
authors.lastname: Horstmann
authors.forename: Hans R
authors.initials: HR
authors.lastname: Widlund
authors.forename: Jinyan
authors.initials: J
authors.lastname: Du
authors.forename: Gabriela
authors.initials: G
authors.lastname: Motyckova
authors.forename: Emi K
authors.initials: EK
authors.lastname: Nishimura
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: William
authors.initials: W
authors.lastname: Avery
authors.forename: Han-Fei
authors.initials: HF
authors.lastname: Ding
authors.forename: Siobhán A
authors.initials: SA
authors.lastname: Jordan
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jackson
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Korsmeyer
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D019070:Cell Lineage; D002469:Cell Separation; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D008544:Melanocytes / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010022:Osteopetrosis / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D014157:Transcription Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D003513:Cycloheximide