Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability.
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.
McGill
Gaël G
GG
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Horstmann
Martin
M
Widlund
Hans R
HR
Du
Jinyan
J
Motyckova
Gabriela
G
Nishimura
Emi K
EK
Lin
Yi-Ling
YL
Ramaswamy
Sridhar
S
Avery
William
W
Ding
Han-Fei
HF
Jordan
Siobhán A
SA
Jackson
Ian J
IJ
Korsmeyer
Stanley J
SJ
Golub
Todd R
TR
Fisher
David E
DE
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
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