The MK5/PRAK Kinase and Myc Form a Negative Feedback Loop that Is Disrupted during Colorectal Tumorigenesis

Theresia R. Kress, Ian G. Cannell, Arjan B. Brenkman, Birgit Samans, Matthias Gaestel, Paul Roepman, Boudewijn M. Burgering, Martin Bushell, Andreas Rosenwald, Martin Eilers

Research output: Contribution to journalArticle

Abstract

Expression of the Myc oncoprotein is downregulated in response to stress signals to allow cells to cease proliferation and escape apoptosis, but the mechanisms involved in this process are poorly understood. Cell cycle arrest in response to DNA damage requires downregulation of Myc via a p53-independent signaling pathway. Here we have used siRNA screening of the human kinome to identify MAPKAPK5 (MK5, PRAK) as a negative regulator of Myc expression. MK5 regulates translation of Myc, since it is required for expression of miR-34b and miR-34c that bind to the 3'UTR of MYC. MK5 activates miR-34b/c expression via phosphorylation of FoxO3a, thereby promoting nuclear localization of FoxO3a and enabling it to induce miR-34b/c expression and arrest proliferation. Expression of MK5 in turn is directly activated by Myc, forming a negative feedback loop. MK5 is downregulated in colon carcinomas, arguing that this feedback loop is disrupted during colorectal tumorigenesis.

Original languageEnglish
Pages (from-to)445-457
Number of pages13
JournalMolecular Cell
Volume41
Issue number4
DOIs
Publication statusPublished - Feb 18 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'The MK5/PRAK Kinase and Myc Form a Negative Feedback Loop that Is Disrupted during Colorectal Tumorigenesis'. Together they form a unique fingerprint.

  • Cite this

    Kress, T. R., Cannell, I. G., Brenkman, A. B., Samans, B., Gaestel, M., Roepman, P., Burgering, B. M., Bushell, M., Rosenwald, A., & Eilers, M. (2011). The MK5/PRAK Kinase and Myc Form a Negative Feedback Loop that Is Disrupted during Colorectal Tumorigenesis. Molecular Cell, 41(4), 445-457. https://doi.org/10.1016/j.molcel.2011.01.023