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Cyclin D3 maintains growth-inhibitory activity of C/EBPalpha by stabilizing C/EBPalpha-cdk2 and C/EBPalpha-Brm complexes

Academic Article
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Overview

authors

  • Wang, G. L.
  • Shi, X. R.
  • Salisbury, E.
  • Sun, Y. X.
  • Albrecht, J. H.
  • Smith, Roy
  • Timchenko, N. A.

publication date

  • 2006

journal

  • Molecular and Cellular Biology  Journal

abstract

  • C/EBPalpha arrests proliferation of young livers by inhibition of cdk2. In old mice, C/EBPalpha inhibits growth by repression of E2F-dependent promoters through the C/EBPalpha-Brm complex. In this paper, we show that cyclin D3-cdk4/cdk6 supports the ability of C/EBPalpha 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/EBPalpha 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/EBPalpha at Ser193 in vitro and in the liver and support growth-inhibitory C/EBPalpha-cdk2 and C/EBPalpha-Brm complexes. We found that cyclin D3 is increased in old livers and activates cdk4/cdk6, resulting in stabilization of the C/EBPalpha-Brm complex. Old livers fail to reduce the activity of cyclin D3-cdk4/cdk6 after partial hepatectomy, leading to high levels of C/EBPalpha-Brm complexes after partial hepatectomy, which correlate with weak proliferation. We examined the role of cyclin D3 in the stabilization of C/EBPalpha-cdk2 and C/EBPalpha-Brm by using 3T3-L1 differentiated cells. In these cells, cyclin D3 is increased during differentiation and phosphorylates C/EBPalpha at Ser193, leading to the formation of growth-inhibitory C/EBPalpha-cdk2 and C/EBPalpha-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/EBPalpha.

subject areas

  • 3T3-L1 Cells
  • Aging
  • Animals
  • CCAAT-Enhancer-Binding Protein-alpha
  • Cell Differentiation
  • Cyclin D3
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Cyclins
  • Growth Inhibitors
  • Hepatectomy
  • Liver
  • Mice
  • Molecular Weight
  • Phosphorylation
  • Protein Binding
  • Protein Isoforms
  • Serine
  • Transcription Factors
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Identity

PubMed Central ID

  • PMC1430318

International Standard Serial Number (ISSN)

  • 0270-7306

Digital Object Identifier (DOI)

  • 10.1128/mcb.26.7.2570-2582.2006

PubMed ID

  • 16537903
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Additional Document Info

start page

  • 2570

end page

  • 2582

volume

  • 26

issue

  • 7

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