D-type cyclins and G1 progression during liver development in the rat.
Initiation and progression through G1 requires the activity of signaling complexes containing cyclins (D- or E-type) and cyclin-dependent kinases (CDK4/6 and CDK2, respectively). We set out to identify the G1-phase cyclins and CDKs that are operative during late gestation liver development in the rat. This is a period during which hepatocytes show a high rate of proliferation that is, at least in part, independent of the mitogenic signaling pathways that are functional in mature hepatocytes. RNase protection assay and Western immunoblotting indicated that cyclin D1 is expressed at similar levels in fetal and adult liver. When cyclin D1 was induced after partial hepatectomy, its predominant CDK-binding partner was CDK4. In contrast, cyclins D2 and D3 predominated in fetal liver and were complexed with both CDK4 and CDK6. Little CDK6 protein was expressed in quiescent or regenerating adult liver. Cyclins E1 and E2 were both transcriptionally up-regulated in fetal liver. Activity of complexes containing cyclins E1 and E2 was higher in fetal liver, as was content of the cell cycle regulator, Rb. In fetal liver, Rb was highly phosphorylated at both cyclin D- and cyclin E-dependent sites. In conclusion, liver development is associated with a switch from cyclin D2/D3-containing complexes to cyclin D1:CDK4 complexes. We speculate that the switch in D-type cyclins may be associated with the dependence on mitogenic signaling that develops as hepatocytes mature.
Boylan
Joan M
JM
Department of Pediatrics, Rhode Island Hospital and Brown University, Providence, RI 02903, USA. Joan_Boylan@brown.edu
Gruppuso
Philip A
PA
D000375:Aging / Q000502:physiology; D000818:Animals; D000906:Antibodies / Q000276:immunology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D056742:Cyclin D2; D056743:Cyclin D3; D019927:Cyclin E / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016193:G1 Phase; D018507:Gene Expression Regulation, Developmental; D047468:Immunoprecipitation; D008099:Liver / Q000166:cytology* / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D008115:Liver Regeneration; D008297:Male; D010766:Phosphorylation; D011247:Pregnancy; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
D000906:Antibodies; C486197:Ccnd2 protein, rat; C534698:Ccnd3 protein, rat; D056742:Cyclin D2; D056743:Cyclin D3; D019927:Cyclin E; D016213:Cyclins; D012333:RNA, Messenger; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases