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

Molecular and Cellular Biology
Guo-Li WangNikolai A Timchenko

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 stab...Continue Reading

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Citations

Dec 18, 2007·Oncogene·N A OlshavskyK E Knudsen
Apr 15, 2008·The Journal of Biological Chemistry·Hyuk C ChaOrmond A MacDougald
Jul 16, 2008·The Journal of Biological Chemistry·Guo-Li WangNikolai A Timchenko
Aug 22, 2007·Molecular and Cellular Biology·Francesca De SantaMaurizia Caruso
Aug 24, 2007·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Melina M MusriMarcelina Párrizas
Jun 2, 2012·American Journal of Respiratory Cell and Molecular Biology·Atsuyasu SatoMachiko Ikegami
Jun 3, 2010·The Journal of Clinical Investigation·Guo-Li WangNikolai A Timchenko
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