FoxM1c counteracts oxidative stress-induced senescence and stimulates Bmi-1 expression.
The Forkhead box transcription factor FoxM1 is expressed in proliferating cells. When it was depleted in mice and cell lines, cell cycle defects and chromosomal instability resulted. Premature senescence was observed in embryonic fibroblasts derived from FoxM1 knock-out mice, but the underlying cause has remained unclear. To investigate whether FoxM1 can protect cells against stress-induced premature senescence, we established NIH3T3 lines with doxycycline-inducible overexpression of FoxM1c. Treatment of these lines with sublethal doses (20 and 100 microm) of H(2)O(2) induced senescence with senescence-associated beta-galactosidase expression and elevated levels of p53 and p21. Induction of FoxM1c expression markedly suppressed senescence and expression of p53 and p21. Consistent with down-regulation of the p19(Arf)-p53 pathway, p19(Arf) levels decreased while expression of the Polycomb group protein Bmi-1 was induced. That Bmi-1 is a downstream target of FoxM1c was further supported by the dose-dependent induction of Bmi-1 by FoxM1c at both the protein and mRNA levels, and FoxM1 and Bmi-1 reached maximal levels in cells at the G(2)/M phase. Depletion of FoxM1 by RNA interference decreased Bmi-1 expression. Using Bmi-1 promoter reporters with wild-type and mutated c-Myc binding sites and short hairpin RNAs targeting c-Myc, we further demonstrated that FoxM1c activated Bmi-1 expression via c-Myc, which was recently reported to be regulated by FoxM1c. Our results reveal a functional link between FoxM1c, c-Myc, and Bmi-1, which are major regulators of tumorigenesis. This link has important implications for the regulation of cell proliferation and senescence by FoxM1 and Bmi-1.
Li
Samuel K M
SK
Department of Biochemistry, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
Smith
David K
DK
Leung
Wai Ying
WY
Cheung
Alice M S
AM
Lam
Eric W F
EW
Dimri
Goberdhan P
GP
Yao
Kwok-Ming
KM
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001665:Binding Sites; D016922:Cellular Senescence; D004318:Doxycycline / Q000494:pharmacology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000900:Anti-Bacterial Agents; C489421:Bmi1 protein, mouse; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D063150:Polycomb Repressive Complex 1; D004318:Doxycycline