TY - JOUR
T1 - Cyclin D3 maintains growth-inhibitory activity of C/EBPα by stabilizing C/EBPα-cdk2 and C/EBPα-Brm complexes
AU - Wang, Guo Li
AU - Shi, Xiurong
AU - Salisbury, Elizabeth
AU - Sun, Yuxiang
AU - Albrecht, Jeffrey H.
AU - Smith, Roy G.
AU - Timchenko, Nikolai A.
PY - 2006/4
Y1 - 2006/4
N2 - C/EBPα arrests proliferation of young livers by inhibition of cdk2. In old mice, C/EBPα inhibits growth by repression of E2F-dcpendent promoters through the C/EBPα-Brm complex. In this paper, we show that cyclin D3-cdk4/cdk6 supports the ability of C/EBPα 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/EBPα 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/EBPα at Ser193 in vitro and in the liver and support growth-inhibitory C/EBPα-cdk2 and C/EBPα-Brm complexes. We found that cyclin D3 is increased in old livers and activates cdk4/cdk6, resulting in stabilization of the C/EBPα-Brm complex. Old livers fail to reduce the activity of cyclin D3-cdk4/cdk6 after partial hepatectomy, leading to high levels of C/EBPα-Brm complexes after partial hepatectomy, which correlate with weak proliferation. We examined the role of cyclin D3 in the stabilization of C/EBPα-cdk2 and C/EBPα-Brm by using 3T3-L1 differentiated cells. In these cells, cyclin D3 is increased during differentiation and phosphorylates C/EBPα at Ser193, leading to the formation of growth-inhibitory C/EBPα-cdk2 and C/EBPα-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/EBPα.
AB - C/EBPα arrests proliferation of young livers by inhibition of cdk2. In old mice, C/EBPα inhibits growth by repression of E2F-dcpendent promoters through the C/EBPα-Brm complex. In this paper, we show that cyclin D3-cdk4/cdk6 supports the ability of C/EBPα 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/EBPα 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/EBPα at Ser193 in vitro and in the liver and support growth-inhibitory C/EBPα-cdk2 and C/EBPα-Brm complexes. We found that cyclin D3 is increased in old livers and activates cdk4/cdk6, resulting in stabilization of the C/EBPα-Brm complex. Old livers fail to reduce the activity of cyclin D3-cdk4/cdk6 after partial hepatectomy, leading to high levels of C/EBPα-Brm complexes after partial hepatectomy, which correlate with weak proliferation. We examined the role of cyclin D3 in the stabilization of C/EBPα-cdk2 and C/EBPα-Brm by using 3T3-L1 differentiated cells. In these cells, cyclin D3 is increased during differentiation and phosphorylates C/EBPα at Ser193, leading to the formation of growth-inhibitory C/EBPα-cdk2 and C/EBPα-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/EBPα.
UR - http://www.scopus.com/inward/record.url?scp=33645226613&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33645226613&partnerID=8YFLogxK
U2 - 10.1128/MCB.26.7.2570-2582.2006
DO - 10.1128/MCB.26.7.2570-2582.2006
M3 - Article
C2 - 16537903
AN - SCOPUS:33645226613
SN - 0270-7306
VL - 26
SP - 2570
EP - 2582
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 7
ER -