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Nature. 2014 Jul 24;511(7510):483-7. doi: 10.1038/nature13473. Epub 2014 Jul 9.

Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles.

Author information

  • 11] Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany [2].
  • 2CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
  • 3Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • 4Institute for Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Str.2, 35033 Marburg, Germany.
  • 5University of Bordeaux, IECB, ARNA laboratory, Equipe Labellisée Contre le Cancer, 33600 Pessac, France.
  • 6Institute for Genetics, Justus-Liebig-University, Heinrich-Buff-Ring 58, 35390 Giessen, Germany.
  • 7University Children's Hospital of Cologne, and Cologne Center for Molecular Medicine (CMMC), University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.
  • 8University Hospital Tübingen, Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, Otfried-Mueller-Strasse 10, 72076 Tübingen, Germany.
  • 91] University Hospital Tübingen, Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, Otfried-Mueller-Strasse 10, 72076 Tübingen, Germany [2] Translational Gastrointestinal Oncology Group within the German Center for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
  • 10DOE Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, California 94598, USA.
  • 111] Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany [2] Rudolf Virchow Center/DFG Research Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Str.2, 97080 Würzburg, Germany [3].
  • 121] Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany [2] Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany [3].

Abstract

In mammalian cells, the MYC oncoprotein binds to thousands of promoters. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes. In contrast, MYC-driven tumour cells differ from normal cells in the expression of specific sets of up- and downregulated genes that have considerable prognostic value. To understand this discrepancy, we studied the consequences of inducible expression and depletion of MYC in human cells and murine tumour models. Changes in MYC levels activate and repress specific sets of direct target genes that are characteristic of MYC-transformed tumour cells. Three factors account for this specificity. First, the magnitude of response parallels the change in occupancy by MYC at each promoter. Functionally distinct classes of target genes differ in the E-box sequence bound by MYC, suggesting that different cellular responses to physiological and oncogenic MYC levels are controlled by promoter affinity. Second, MYC both positively and negatively affects transcription initiation independent of its effect on transcriptional elongation. Third, complex formation with MIZ1 (also known as ZBTB17) mediates repression of multiple target genes by MYC and the ratio of MYC and MIZ1 bound to each promoter correlates with the direction of response.

PMID:
25043018
[PubMed - in process]
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