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Inducible and Reversible Dominant-negative (DN) Protein Inhibition
08:35

Inducible and Reversible Dominant-negative (DN) Protein Inhibition

Published on: January 7, 2019

Dominant-negative TAK1 induces c-Myc and G(0) exit in liver

C A Bradham1, E Hatano, D A Brenner

  • 1Department of Medicine, University of North Carolina at Chapel Hill, 27707, USA.

American Journal of Physiology. Gastrointestinal and Liver Physiology
|October 23, 2001
PubMed

Insights

Transforming growth factor-beta-activated kinase 1 (TAK1) is crucial for liver cell cycle regulation. Inhibiting TAK1 in rats promoted cell cycle entry and progression, mediated by c-myc induction.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Hepatology

Background:

  • Transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1) is a kinase involved in TGF-beta, interleukin-1, and ceramide signaling pathways.
  • The precise physiological role of TAK1 in vivo remains largely uncharacterized.

Purpose of the Study:

  • To investigate the in vivo function of TAK1 in liver physiology.
  • To elucidate TAK1's role in cell cycle regulation and signaling pathways within the liver.

Main Methods:

  • Adenoviral gene transfer was used to express dominant-negative TAK1 (dnTAK1) in rat liver.
  • Partial hepatectomy (PH) was performed to stimulate liver regeneration.
  • Activation of signaling pathways including c-Jun NH(2)-terminal kinase, c-Jun, nuclear factor (NF)-kappaB, and SMAD was assessed.
  • Expression of c-myc was analyzed before and after PH.

Main Results:

  • dnTAK1 expression inhibited c-Jun NH(2)-terminal kinase and c-Jun activation post-PH, but not NF-kappaB or SMAD activation.
  • Expression of dnTAK1 or TAM-67 (a dominant-negative c-Jun) induced G(0) exit in quiescent liver cells.
  • dnTAK1 and TAM-67 accelerated cell cycle progression following PH.
  • Both dnTAK1 and TAM-67 induced c-myc expression in the liver, both before and after PH.

Conclusions:

  • TAK1 plays a significant role in regulating liver cell cycle progression.
  • The G(0) exit induced by TAK1 inhibition is mediated through the induction of c-myc.
  • TAK1 is a key regulator of liver regeneration and cell proliferation via c-myc.

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