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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 by Stabilizing C/EBP-cdk2 and C/EBP-Brm Complexes

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

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