Intact signaling by transforming growth factor β is not required for termination of liver regeneration in mice
Autor: | Jonas Larsson, Shoshiro Oe, Elizabeth A. Conner, Snorri S. Thorgeirsson, Eric R. Lemmer, Valentina M. Factor, Per Levéen, Stefan Karlsson |
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Rok vydání: | 2004 |
Předmět: |
Follistatin
medicine.medical_specialty Smad Proteins SMAD Protein Serine-Threonine Kinases Biology Transforming Growth Factor beta1 Mice Cyclin D1 Transforming Growth Factor beta Internal medicine Conditional gene knockout medicine Animals Inhibin-beta Subunits Mice Knockout Hepatology Receptor Transforming Growth Factor-beta Type II DNA Transforming growth factor beta Liver regeneration Activins Liver Regeneration Cell biology DNA-Binding Proteins medicine.anatomical_structure Endocrinology Hepatocyte Hepatocytes Trans-Activators biology.protein Receptors Transforming Growth Factor beta Cell Division Signal Transduction Transforming growth factor |
Zdroj: | Hepatology. 40:1098-1105 |
ISSN: | 0270-9139 |
Popis: | Transforming growth factor beta (TGF-beta) is a potent inhibitor of hepatocyte proliferation in vitro and is suggested to be a key negative regulator of liver growth. To directly address the role of TGF-beta signaling in liver regeneration in vivo, the TGF-beta type II receptor gene (Tgfbr2) was selectively deleted in hepatocytes by crossing "floxed" Tgfbr2 conditional knockout mice with transgenic mice expressing Cre under control of the albumin promoter. Hepatocytes isolated from liver-specific Tgfbr2 knockout (R2LivKO) mice were refractory to the growth inhibitory effects of TGF-beta1. The peak of DNA synthesis after 70% partial hepatectomy occurred earlier (36 vs. 48 hours) and was 1.7-fold higher in R2LivKO mice compared with controls. Accelerated S-phase entry by proliferating R2LivKO hepatocytes coincided with the hyperphosphorylation of Rb protein and the early upregulation of cyclin D1 and cyclin E. However, by 120 hours after partial hepatectomy, hepatocyte proliferation was back to baseline in both control and R2LivKO liver. Regenerating R2LivKO liver showed evidence of increased signaling by activin A and persistent activity of the Smad pathway. Blockage of activin A signaling by the specific inhibitor follistatin resulted in increased hepatocyte proliferation at 120 hours, particularly in R2LivKO livers. In conclusion, TGF-beta regulates G(1) to S phase transition of hepatocytes, but intact signaling by TGF-beta is not required for termination of liver regeneration. Increased signaling by activin A may compensate to regulate liver regeneration when signaling through the TGF-beta pathway is abolished, and may be a principal factor in the termination of liver regeneration. |
Databáze: | OpenAIRE |
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