title: c-MYC targets the central oscillator gene Per1 and is regulated by the circadian clock at the post-transcriptional level.
abstract: Cell proliferation in mammals follows a circadian rhythm while disruption of clock gene expression has been linked to tumorigenesis. Expression of the c-Myc oncogene is frequently deregulated in tumors, facilitating aberrant cell proliferation. c-MYC protein levels display circadian rhythmicity, which is compatible with an in vitro repressive role of the clock-activating complex BMAL1/CLOCK on its promoter. In this report, we provide evidence for the in vivo binding of the core circadian factor BMAL1 on the human c-Myc promoter. In addition, analysis of protein synthesis and degradation rates, as well as post-translational acetylation, demonstrate that the clock tightly controls cellular MYC levels. The oncoprotein itself is a transcription factor that by responding to mitogenic signals regulates the expression of several hundred genes. c-MYC-driven transcription is generally exerted upon dimerization with MAX and binding to E-box elements, a sequence that is also recognized by the circadian heterodimer. Our reporter assays reveal that the MYC/MAX dimer cannot affect transcription of the circadian gene Per1. However, when overexpressed, c-MYC is able to repress Per1 transactivation by BMAL1/CLOCK via targeting selective E-box sequences. Importantly, upon serum stimulation, MYC was detected in BMAL1 protein complexes. Together, these data demonstrate a novel interaction between MYC and circadian transactivators resulting in reduced clock-driven transcription. Perturbation of Per1 expression by MYC constitutes a plausible alternative explanation for the deregulated expression of clock genes observed in many types of cancer.
authors: Institute of Biosciences and Applications, Laboratory of Chronobiology, NCSR 'Demokritos', 15310 Aghia Paraskevi, Attiki, Greece. Electronic address: arepouskou@bio.demokritos.gr.
authors: Anastasia
authors: A
authors: Repouskou
authors: Institute of Biosciences and Applications, Laboratory of Chronobiology, NCSR 'Demokritos', 15310 Aghia Paraskevi, Attiki, Greece. Electronic address: prombona@bio.demokritos.gr.
authors: Anastasia
authors: A
authors: Prombona
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D056926:CLOCK Proteins / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D024721:E-Box Elements / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009447:Neuroblastoma; D056950:Period Circadian Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D060066:Protein Interaction Maps; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499330:MAX protein, human; C489427:MYC protein, human; C539022:PER1 protein, human; D056950:Period Circadian Proteins; D016271:Proto-Oncogene Proteins c-myc; D056926:CLOCK Proteins
keywords: Circadian; Per-1; Protein–protein interaction; Transcriptional regulation; c-MYC