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A more recent version of this article appeared on February 1, 2007
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Submitted on May 22, 2006
Revised on November 14, 2006
Accepted on November 27, 2006
*Division of Cancer Biology and Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, and Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, IL 60201
Monitoring Editor: John Cleveland
Polycomb group (PcG) protein Bmi-1 is an important regulator of cell proliferation. It regulates cellular senescence and proliferation of cells via the transcriptional repression of INK4a/ARF locus and other target genes. Here, we report that Mel-18, a PcG ring finger protein (PCGF) transcriptionally downregulates Bmi-1. Furthermore, the expression of Bmi-1 and Mel-18 inversely correlates in proliferating and senescent human fibroblasts. Bmi-1 down-regulation by Mel-18 results in accelerated senescence and shortening of the replicative life span in normal human cells. Importantly, using promoter-reporter, chromatin immunoprecipitation (ChIP) and quantitative real time primary transcript RT-PCR (PT RT-PCR) assays, and an RNA interference (RNAi) approach, we demonstrate that Bmi-1 is a bona fide target of c-Myc oncoprotein. Finally, our data suggest that Mel-18 regulates Bmi-1 expression during senescence via down-regulation of c-Myc. These studies link c-Myc and polycomb function in cell proliferation and senescence.
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