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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.
Abstract:
Transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1), a serine/threonine kinase, is reported to function in the signaling pathways of TGF-beta, interleukin 1, and ceramide. However, the physiological role of TAK1 in vivo is largely unknown. To assess the function of TAK1 in vivo, dominant-negative TAK1 (dnTAK1) was expressed in the rat liver by adenoviral gene transfer. dnTAK1 expression abrogated c-Jun NH(2)-terminal kinase and c-Jun but not nuclear factor (NF)-kappaB or SMAD activation after partial hepatectomy (PH). Expression of dnTAK1 or TAM-67, a dominant-negative c-Jun, induced G(0) exit in quiescent liver and accelerated cell cycle progression after PH. Finally, dnTAK1 and TAM-67 induced c-myc expression in the liver before and after PH, suggesting that G(0) exit induced by dnTAK1 and TAM-67 is mediated by c-myc induction.
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.