This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Jin, J.
Right arrow Articles by Timchenko, N. A.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jin, J.
Right arrow Articles by Timchenko, N. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2009, p. 3867-3880, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.00456-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Age-Associated Decline of Glycogen Synthase Kinase 3β Plays a Critical Role in the Inhibition of Liver Regeneration{triangledown}

Jingling Jin, Guo-Li Wang, Xiurong Shi, Gretchen J. Darlington, and Nikolai A. Timchenko*

Huffington Center on Aging and Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030

Received 8 April 2009/ Accepted 17 April 2009

Aging reduces the regenerative capacities of many tissues. In this paper, we show a critical role of the glycogen synthase kinase 3β (GSK3β)-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 GSK3β, which associates with cyclin D3 and triggers degradation of cyclin D3. In livers of old mice, the GSK3β promoter is repressed by C/EBPβ-histone deacetylase 1 (HDAC1) complexes, leading to the reduction of GSK3β. The treatment of old mice with GH increases expression of GSK3β via removal of the C/EBPβ-HDAC1 complexes from the GSK3β promoter. We found that the GSK3β-cyclin D3 pathway is also altered in young GH-deficient Little mice and that treatment of Little mice with GH corrects the GSK3β-cyclin D3 pathway. We present evidence that GSK3β regulates liver proliferation by controlling growth-inhibitory activity of C/EBP{alpha}. The downregulation of GSK3β in young mice inhibits liver proliferation after partial hepatectomy via the cyclin D3-C/EBP{alpha} pathway, while the elevation of GSK3β in old mice accelerates liver proliferation. Thus, this paper shows that GSK3β is a critical regulator of liver proliferation and that the reduction of GSK3β with age causes the loss of regenerative capacities of the liver.

* Corresponding author. Mailing address: Department of Pathology and Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-1567. Fax: (713) 798-4161. E-mail: nikolait{at}bcm.tmc.edu

{triangledown} Published ahead of print on 27 April 2009.

Molecular and Cellular Biology, July 2009, p. 3867-3880, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.00456-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»