| First Author | Repouskou A | Year | 2016 |
| Journal | Biochim Biophys Acta | Volume | 1859 |
| Issue | 4 | Pages | 541-52 |
| PubMed ID | 26850841 | Mgi Jnum | J:257190 |
| Mgi Id | MGI:6106138 | Doi | 10.1016/j.bbagrm.2016.02.001 |
| Citation | Repouskou A, et al. (2016) c-MYC targets the central oscillator gene Per1 and is regulated by the circadian clock at the post-transcriptional level. Biochim Biophys Acta 1859(4):541-52 |
| abstractText | 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. |
