Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability

Gaël G. McGill, Martin Horstmann, Hans R. Widlund, Jinyan Du, Gabriela Motyckova, Emi K. Nishimura, Yi Ling Lin, Sridhar Ramaswamy, William Avery, Han Fei Ding, Siobhán A. Jordan, Ian J. Jackson, Stanley J. Korsmeyer, Todd R. Golub, David E. Fisher

Research output: Contribution to journalArticle

542 Scopus citations

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 Mitfmi/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.

Original languageEnglish (US)
Pages (from-to)707-718
Number of pages12
JournalCell
Volume109
Issue number6
DOIs
StatePublished - Jun 14 2002

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    McGill, G. G., Horstmann, M., Widlund, H. R., Du, J., Motyckova, G., Nishimura, E. K., Lin, Y. L., Ramaswamy, S., Avery, W., Ding, H. F., Jordan, S. A., Jackson, I. J., Korsmeyer, S. J., Golub, T. R., & Fisher, D. E. (2002). Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell, 109(6), 707-718. https://doi.org/10.1016/S0092-8674(02)00762-6