Cyclin D3 maintains growth-inhibitory activity of C/EBPalpha by stabilizing C/EBPalpha-cdk2 and C/EBPalpha-Brm complexes. Academic Article uri icon

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.

published proceedings

  • Mol Cell Biol

author list (cited authors)

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

citation count

  • 62

complete list of authors

  • Wang, Guo-Li||Shi, Xiurong||Salisbury, Elizabeth||Sun, Yuxiang||Albrecht, Jeffrey H||Smith, Roy G||Timchenko, Nikolai A

publication date

  • April 2006