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Article: FoxM1c counteracts oxidative stress-induced senescence and stimulates Bmi-1 expression

TitleFoxM1c counteracts oxidative stress-induced senescence and stimulates Bmi-1 expression
Authors
Issue Date2008
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 2008, v. 283 n. 24, p. 16545-16553 How to Cite?
AbstractThe 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 μM) of H 2O 2 induced senescence with senescence-associated β-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. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/68092
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLi, SKMen_HK
dc.contributor.authorSmith, DKen_HK
dc.contributor.authorLeung, WYen_HK
dc.contributor.authorCheung, AMSen_HK
dc.contributor.authorLam, EWFen_HK
dc.contributor.authorDimri, GPen_HK
dc.contributor.authorYao, KMen_HK
dc.date.accessioned2010-09-06T06:01:16Z-
dc.date.available2010-09-06T06:01:16Z-
dc.date.issued2008en_HK
dc.identifier.citationJournal Of Biological Chemistry, 2008, v. 283 n. 24, p. 16545-16553en_HK
dc.identifier.issn0021-9258en_HK
dc.identifier.urihttp://hdl.handle.net/10722/68092-
dc.description.abstractThe 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 μM) of H 2O 2 induced senescence with senescence-associated β-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. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.en_HK
dc.languageengen_HK
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_HK
dc.relation.ispartofJournal of Biological Chemistryen_HK
dc.rightsJournal of Biological Chemistry. Copyright © American Society for Biochemistry and Molecular Biology, Inc.en_HK
dc.rightsThis research was originally published in Journal of Biological Chemistry. Li, SKM, Smith, DK, Leung, WY et al. FoxM1c counteracts oxidative stress-induced senescence and stimulates Bmi-1 expression. Journal of Biological Chemistry. 2008, v. 283 n. 24, p. 16545-16553. © the American Society for Biochemistry and Molecular Biology-
dc.subject.meshForkhead Transcription Factors - metabolism - physiology-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshNuclear Proteins - metabolism - physiology-
dc.subject.meshProto-Oncogene Proteins - metabolism - physiology-
dc.subject.meshRepressor Proteins - metabolism - physiology-
dc.titleFoxM1c counteracts oxidative stress-induced senescence and stimulates Bmi-1 expressionen_HK
dc.typeArticleen_HK
dc.identifier.emailCheung, AMS:h9945256@graduate.hku.hken_HK
dc.identifier.emailYao, KM:kmyao@hku.hken_HK
dc.identifier.authorityCheung, AMS=rp01572en_HK
dc.identifier.authorityYao, KM=rp00344en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1074/jbc.M709604200en_HK
dc.identifier.pmid18408007-
dc.identifier.pmcidPMC2423239-
dc.identifier.scopuseid_2-s2.0-47749108741en_HK
dc.identifier.hkuros200891en_HK
dc.identifier.hkuros144989-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-47749108741&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume283en_HK
dc.identifier.issue24en_HK
dc.identifier.spage16545en_HK
dc.identifier.epage16553en_HK
dc.identifier.eissn1083-351X-
dc.identifier.isiWOS:000256497100031-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLi, SKM=9273056900en_HK
dc.identifier.scopusauthoridSmith, DK=7410351143en_HK
dc.identifier.scopusauthoridLeung, WY= 7201504543en_HK
dc.identifier.scopusauthoridCheung, AMS=36985759800en_HK
dc.identifier.scopusauthoridLam, EWF=7102889877en_HK
dc.identifier.scopusauthoridDimri, GP=6701892352en_HK
dc.identifier.scopusauthoridYao, KM=7403234578en_HK
dc.identifier.citeulike9756284-

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