title: Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via upregulation of the core clock protein, BMAL1.
abstract: Selenium compounds are known as cancer preventive agents and are also able to ameliorate the toxicity associated with anti-cancer radiation and chemotherapy in mouse models. Sensitivity to the toxicity of chemotherapy is also modulated by the circadian clock, molecular time-keeping system that underlie daily fluctuations in multiple physiological and biochemical processes. Here we show that these two mechanisms are interconnected. By screening a library of small molecules in a cell-based reporter system, we identified L-methyl-selenocysteine as a positive regulator of the core clock protein, BMAL1. L-methyl-selenocysteine up-regulates BMAL1 at the transcriptional level both in cultured cells and in mice. We also show that in tissue culture selenium exerts its action by interfering with TIEG1-mediated repression of Bmal1 promoter. Selenium treatment fails to protect BMAL1-deficient mice from toxicity induced by the chemotherapeutic agent cyclophosphamide but does protect Clock mutant mice deficient in circadian rhythm control but having normal BMAL1. These findings define selenium as circadian modulator and indicate that the tissue protective effect of selenium results, at least in part, from up-regulation of BMAL1 expression and subsequent enhancement of CLOCK/BMAL1-mediated transcription.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hu
authors.forename: Mary L
authors.initials: ML
authors.lastname: Spengler
authors.forename: Karen K
authors.initials: KK
authors.lastname: Kuropatwinski
authors.forename: Maria
authors.initials: M
authors.lastname: Comas-Soberats
authors.forename: Marilyn
authors.initials: M
authors.lastname: Jackson
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Chernov
authors.forename: Anatoly S
authors.initials: AS
authors.lastname: Gleiberman
authors.forename: Natalia
authors.initials: N
authors.lastname: Fedtsova
authors.forename: Youcef M
authors.initials: YM
authors.lastname: Rustum
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Marina P
authors.initials: MP
authors.lastname: Antoch
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D057906:Circadian Clocks; D003520:Cyclophosphamide / Q000009:adverse effects / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D016566:Organoselenium Compounds / Q000494:pharmacology; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D018036:Selenium Compounds / Q000494:pharmacology*; D017279:Selenocysteine / Q000031:analogs & derivatives; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors
chemical_list: D056930:ARNTL Transcription Factors; D056926:CLOCK Proteins; D003520:Cyclophosphamide; D003545:Cysteine; D004268:DNA-Binding Proteins; D016566:Organoselenium Compounds; D056950:Period Circadian Proteins; D034741:RNA, Small Interfering; D018036:Selenium Compounds; D017279:Selenocysteine; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C539023:Per1 protein, mouse; C538944:Clock protein, mouse; C002979:selenomethylselenocysteine; C569958:KLF10 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors