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
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wang, G.-L.
Right arrow Articles by Timchenko, N. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wang, G.-L.
Right arrow Articles by Timchenko, N. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 2006, p. 2570-2582, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2570-2582.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cyclin D3 Maintains Growth-Inhibitory Activity of C/EBP{alpha} by Stabilizing C/EBP{alpha}-cdk2 and C/EBP{alpha}-Brm Complexes

Guo-Li Wang,1,2 Xiurong Shi,1 Elizabeth Salisbury,1 Yuxiang Sun,1 Jeffrey H. Albrecht,4 Roy G. Smith,1,3 and Nikolai A. Timchenko1,2*

Huffington Center on Aging,1 Departments of Pathology,2 Molecular Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030,3 Division of Gastroenterology, Hennepin County Medical Center, Minneapolis, Minnesota 554154

Received 5 December 2005/ Accepted 5 January 2006

C/EBP{alpha} arrests proliferation of young livers by inhibition of cdk2. In old mice, C/EBP{alpha} inhibits growth by repression of E2F-dependent promoters through the C/EBP{alpha}-Brm complex. In this paper, we show that cyclin D3-cdk4/cdk6 supports the ability of C/EBP{alpha} to inhibit liver proliferation in both age groups. Although cyclin D3-cdk4/cdk6 kinases are involved in the promotion of growth, they are expressed in terminally differentiated cells, suggesting that they have additional functions in these settings. We demonstrate that C/EBP{alpha} represents a target for phosphorylation by cyclin D3-cdk4/cdk6 complexes in differentiated liver cells and in differentiated adipocytes. Cyclin D3-cdk4/cdk6 specifically phosphorylate C/EBP{alpha} at Ser193 in vitro and in the liver and support growth-inhibitory C/EBP{alpha}-cdk2 and C/EBP{alpha}-Brm complexes. We found that cyclin D3 is increased in old livers and activates cdk4/cdk6, resulting in stabilization of the C/EBP{alpha}-Brm complex. Old livers fail to reduce the activity of cyclin D3-cdk4/cdk6 after partial hepatectomy, leading to high levels of C/EBP{alpha}-Brm complexes after partial hepatectomy, which correlate with weak proliferation. We examined the role of cyclin D3 in the stabilization of C/EBP{alpha}-cdk2 and C/EBP{alpha}-Brm by using 3T3-L1 differentiated cells. In these cells, cyclin D3 is increased during differentiation and phosphorylates C/EBP{alpha} at Ser193, leading to the formation of growth-inhibitory C/EBP{alpha}-cdk2 and C/EBP{alpha}-Brm complexes. The inhibition of cyclin D3 blocks the formation of these complexes. Thus, these studies provide a new function of cyclin D3, which is to support the growth-inhibitory activity of C/EBP{alpha}.

* 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.

Molecular and Cellular Biology, April 2006, p. 2570-2582, Vol. 26, No. 7
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.7.2570-2582.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Jin, J., Wang, G.-L., Shi, X., Darlington, G. J., Timchenko, N. A. (2009). The Age-Associated Decline of Glycogen Synthase Kinase 3{beta} Plays a Critical Role in the Inhibition of Liver Regeneration. Mol. Cell. Biol. 29: 3867-3880 [Abstract] [Full Text]  
  • Ren, J., Hascall, V. C., Wang, A. (2009). Cyclin D3 Mediates Synthesis of a Hyaluronan Matrix That Is Adhesive for Monocytes in Mesangial Cells Stimulated to Divide in Hyperglycemic Medium. J. Biol. Chem. 284: 16621-16632 [Abstract] [Full Text]  
  • Wang, G.-L., Salisbury, E., Shi, X., Timchenko, L., Medrano, E. E., Timchenko, N. A. (2008). HDAC1 Cooperates with C/EBP{alpha} in the Inhibition of Liver Proliferation in Old Mice. J. Biol. Chem. 283: 26169-26178 [Abstract] [Full Text]  
  • Cha, H. C., Oak, N. R., Kang, S., Tran, T.-A., Kobayashi, S., Chiang, S.-H., Tenen, D. G., MacDougald, O. A. (2008). Phosphorylation of CCAAT/Enhancer-binding Protein {alpha} Regulates GLUT4 Expression and Glucose Transport in Adipocytes. J. Biol. Chem. 283: 18002-18011 [Abstract] [Full Text]  
  • De Santa, F., Albini, S., Mezzaroma, E., Baron, L., Felsani, A., Caruso, M. (2007). pRb-Dependent Cyclin D3 Protein Stabilization Is Required for Myogenic Differentiation. Mol. Cell. Biol. 27: 7248-7265 [Abstract] [Full Text]  
  • Datta, J., Majumder, S., Kutay, H., Motiwala, T., Frankel, W., Costa, R., Cha, H. C., MacDougald, O. A., Jacob, S. T., Ghoshal, K. (2007). Metallothionein Expression Is Suppressed in Primary Human Hepatocellular Carcinomas and Is Mediated through Inactivation of CCAAT/Enhancer Binding Protein {alpha} by Phosphatidylinositol 3-Kinase Signaling Cascade. Cancer Res. 67: 2736-2746 [Abstract] [Full Text]  
  • Wang, G.-L., Shi, X., Salisbury, E., Sun, Y., Albrecht, J. H., Smith, R. G., Timchenko, N. A. (2007). Growth Hormone Corrects Proliferation and Transcription of Phosphoenolpyruvate Carboxykinase in Livers of Old Mice via Elimination of CCAAT/Enhancer-binding Protein {alpha}-Brm Complex. J. Biol. Chem. 282: 1468-1478 [Abstract] [Full Text]  
  • Yamasaki, H., Sada, A., Iwata, T., Niwa, T., Tomizawa, M., Xanthopoulos, K. G., Koike, T., Shiojiri, N. (2006). Suppression of C/EBP{alpha} expression in periportal hepatoblasts may stimulate biliary cell differentiation through increased Hnf6 and Hnf1b expression. Development 133: 4233-4243 [Abstract] [Full Text]  
  • Timchenko, L. T., Salisbury, E., Wang, G.-L., Nguyen, H., Albrecht, J. H., Hershey, J. W. B., Timchenko, N. A. (2006). Age-specific CUGBP1-eIF2 Complex Increases Translation of CCAAT/Enhancer-binding Protein beta in Old Liver. J. Biol. Chem. 281: 32806-32819 [Abstract] [Full Text]  


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