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Cyclin D2 Compensates for the Loss of Cyclin D1 in Estrogen-Induced Mouse Uterine Epithelial Cell Proliferation

Departments of Developmental and Molecular Biology and Obstetrics, Gynecology and Women’s Health, Center for the Study of Reproductive Biology and Women’s Health, Albert Einstein College of Medicine, New York, New York 10461

Address all correspondence and requests for reprints to:Jeffrey W. Pollard, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, New York 10461. E-mail: pollard{at}aecom.yu.edu; bochen{at}aecom.yu.edu.

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 17ß-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 p27^kip1 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   PR

Coregulators:   Rb  |  Cyclin D1

Ligands:   17β-Estradiol

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