title: MYC/MIZ1-dependent gene repression inversely coordinates the circadian clock with cell cycle and proliferation.
abstract: The circadian clock and the cell cycle are major cellular systems that organize global physiology in temporal fashion. It seems conceivable that the potentially conflicting programs are coordinated. We show here that overexpression of MYC in U2OS cells attenuates the clock and conversely promotes cell proliferation while downregulation of MYC strengthens the clock and reduces proliferation. Inhibition of the circadian clock is crucially dependent on the formation of repressive complexes of MYC with MIZ1 and subsequent downregulation of the core clock genes BMAL1 (ARNTL), CLOCK and NPAS2. We show furthermore that BMAL1 expression levels correlate inversely with MYC levels in 102 human lymphomas. Our data suggest that MYC acts as a master coordinator that inversely modulates the impact of cell cycle and circadian clock on gene expression.
authors.affiliation: Heidelberg University, Biochemistry Center, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.
authors.forename: Anton
authors.initials: A
authors.lastname: Shostak
authors.affiliation: Heidelberg University, Biochemistry Center, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Ruppert
authors.affiliation: Heidelberg University, Biochemistry Center, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.
authors.forename: Nati
authors.initials: N
authors.lastname: Ha
authors.affiliation: Division Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Bruns
authors.affiliation: Division Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Umut H
authors.initials: UH
authors.lastname: Toprak
authors.affiliation: Division Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.|Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.affiliation: Division Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlesner
authors.affiliation: Heidelberg University, Biochemistry Center, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Diernfellner
authors.affiliation: Heidelberg University, Biochemistry Center, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Brunner
mesh_terms: D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology*; D057906:Circadian Clocks / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008223:Lymphoma / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*
chemical_list: D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C107961:ZBTB17 protein, human