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Vol. 18, Issue 2, 536-546, February 2007
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*Division of Cancer Biology and Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, and Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, IL 60201
Submitted May 22, 2006;
Revised November 14, 2006;
Accepted September 27, 2006
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 down-regulates 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, and quantitative real-time primary transcript RT-PCR assays, and an RNA interference 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.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Address correspondence to: Goberdhan P. Dimri (g-dimri{at}northwestern.edu)
This article has been cited by other articles:
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J.-Y. Lee, K.-S. Jang, D.-H. Shin, M.-Y. Oh, H.-J. Kim, Y. Kim, and G. Kong Mel-18 Negatively Regulates INK4a/ARF-Independent Cell Cycle Progression via Akt Inactivation in Breast Cancer Cancer Res., June 1, 2008; 68(11): 4201 - 4209. [Abstract] [Full Text] [PDF]
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S. Datta, M. J. Hoenerhoff, P. Bommi, R. Sainger, W.-J. Guo, M. Dimri, H. Band, V. Band, J. E. Green, and G. P. Dimri Bmi-1 Cooperates with H-Ras to Transform Human Mammary Epithelial Cells via Dysregulation of Multiple Growth-Regulatory Pathways Cancer Res., November 1, 2007; 67(21): 10286 - 10295. [Abstract] [Full Text] [PDF]
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