The age-associated decline of glycogen synthase kinase 3beta plays a critical role in the inhibition of liver regeneration.
Aging reduces the regenerative capacities of many tissues. In this paper, we show a critical role of the glycogen synthase kinase 3beta (GSK3beta)-cyclin D3 pathway in the loss of the regenerative capacity of the liver. In young animals, high levels of growth hormone (GH) increase expression of GSK3beta, which associates with cyclin D3 and triggers degradation of cyclin D3. In livers of old mice, the GSK3beta promoter is repressed by C/EBPbeta-histone deacetylase 1 (HDAC1) complexes, leading to the reduction of GSK3beta. The treatment of old mice with GH increases expression of GSK3beta via removal of the C/EBPbeta-HDAC1 complexes from the GSK3beta promoter. We found that the GSK3beta-cyclin D3 pathway is also altered in young GH-deficient Little mice and that treatment of Little mice with GH corrects the GSK3beta-cyclin D3 pathway. We present evidence that GSK3beta regulates liver proliferation by controlling growth-inhibitory activity of C/EBPalpha. The downregulation of GSK3beta in young mice inhibits liver proliferation after partial hepatectomy via the cyclin D3-C/EBPalpha pathway, while the elevation of GSK3beta in old mice accelerates liver proliferation. Thus, this paper shows that GSK3beta is a critical regulator of liver proliferation and that the reduction of GSK3beta with age causes the loss of regenerative capacities of the liver.
Jin
Jingling
J
Department of Pathology and Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Wang
Guo-Li
GL
Shi
Xiurong
X
Darlington
Gretchen J
GJ
Timchenko
Nikolai A
NA
D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D056743:Cyclin D3; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D013006:Growth Hormone / Q000172:deficiency / Q000627:therapeutic use; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008115:Liver Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000494:pharmacology
D022763:CCAAT-Enhancer-Binding Protein-alpha; C534696:CCND3 protein, human; C534697:Ccnd3 protein, mouse; D056743:Cyclin D3; D016213:Cyclins; D017931:DNA Primers; D011994:Recombinant Proteins; D013006:Growth Hormone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases