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A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
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A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer

Published on: July 6, 2017

The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis

Theresia R Kress1, Ian G Cannell, Arjan B Brenkman

  • 1Theodor-Boveri-Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.

Molecular Cell
|February 19, 2011
PubMed

Insights

Stress signals downregulate Myc to halt cell growth, but mechanisms were unclear. Researchers identified MAPKAPK5 (MK5) as a key regulator of Myc translation, crucial for cell cycle arrest and potentially disrupted in colon cancer.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Myc oncoprotein downregulation is essential for stress-induced cell cycle arrest and apoptosis evasion.
  • The precise molecular mechanisms governing Myc suppression, particularly via p53-independent pathways, remain largely unelucidated.
  • Understanding these pathways is critical for comprehending cancer development and progression.

Purpose of the Study:

  • To identify novel regulators of Myc expression involved in stress response.
  • To elucidate the signaling pathway through which Myc is downregulated.
  • To investigate the role of identified regulators in colorectal tumorigenesis.

Main Methods:

  • siRNA screening of the human kinome to identify negative regulators of Myc.
  • Analysis of microRNA (miR-34b/c) expression and their binding to MYC 3'UTR.
  • Investigation of the role of MAPKAPK5 (MK5) in FoxO3a phosphorylation and nuclear localization.
  • Assessment of MK5 expression in colon carcinoma tissues.

Main Results:

  • siRNA screening identified MAPKAPK5 (MK5) as a negative regulator of Myc expression.
  • MK5 controls Myc translation by regulating miR-34b and miR-34c expression.
  • MK5 phosphorylates FoxO3a, promoting its nuclear translocation and subsequent induction of miR-34b/c, leading to cell proliferation arrest.
  • A negative feedback loop exists where Myc activates MK5 expression, which in turn suppresses Myc.
  • MK5 is downregulated in colon carcinomas, suggesting disruption of this feedback loop in colorectal cancer.

Conclusions:

  • MAPKAPK5 (MK5) is a crucial negative regulator of Myc expression, operating through the miR-34b/c and FoxO3a pathway.
  • This MK5-mediated pathway is vital for Myc-induced cell cycle arrest.
  • Disruption of the Myc-MK5 feedback loop due to MK5 downregulation may contribute to colorectal tumorigenesis.

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