Cyclin D2 compensates for the loss of cyclin D1 in estrogen-induced mouse uterine epithelial cell proliferation.
The cell cycle-regulatory protein, cyclin D1, is the sensor that connects the intracellular cell cycle machinery to external signals. Given this central role in the control of cell proliferation, it was surprising that mice lacking the cyclin D1 gene were viable and fertile. Fertility requires 17beta-estradiol (E2)-induced uterine luminal epithelial cell proliferation. In these cells E2 causes the translocation of cyclin D1/cyclin-dependent kinase 4 (CDK4) from the cytoplasm into the nucleus with the consequent phosphorylation of the retinoblastoma protein. In cyclin D1 null mice, E2 also induces retinoblastoma protein phosphorylation and DNA synthesis in a normal manner. CDK4 activity was slightly reduced in the D1 null mice compared with wild-type mice. This CDK4 activity was due to complexes of cyclin D2/CDK4. Cyclin D2 was translocated into the nucleus in response to E2 in the cyclin D1-/- mice to a much greater degree than in wild-type mice. This cyclin D2/CDK4 complex was also able to bind p27kip1 in cyclin D1-/- uterine luminal epithelial cells, allowing for the activation of CDK2. Our data show that in vivo cyclin D2 can completely compensate for the loss of cyclin D1 and reinforces the conclusions that cyclin Ds are the central regulatory point in the proliferative responses of epithelial cells to estrogens.
Chen
Bo
B
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York 10461, USA. bochen@aecom.yu.edu
Pollard
Jeffrey W
JW
D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D056742:Cyclin D2; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D011980:Receptors, Progesterone / Q000187:drug effects / Q000235:genetics; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014599:Uterus / Q000166:cytology* / Q000187:drug effects / Q000502:physiology
C486196:Ccnd2 protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D011980:Receptors, Progesterone; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004958:Estradiol; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases