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Molecular and Cellular Biology, February 2001, p. 1319-1328, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1319-1328.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Genetic Evidence for the Interactions of Cyclin D1 and p27Kip1 in Mice

Wei Tongdagger and Jeffrey W. Pollard*

Departments of Developmental and Molecular Biology and Obstetrics and 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

Received 17 July 2000/Returned for modification 7 September 2000/Accepted 14 November 2000

The cell cycle of cultured cells appears to be regulated by opposing actions of the cyclins together with their partners, the cyclin-dependent kinases (Cdk), and their inhibitors (Cki). Consistent with this situation null mutations in the genes for cyclin D1 and Cki p27Kip1 in mice give opposite phenotypes of dwarfism and gigantism. To test their genetic interactions, we generated mice nullizygous for both genes. Correction of cyclin D1 or p27 null to wild-type phenotypes was observed for many but not all traits. These included, for cyclin D1-/- mice, body weight, early lethality, retinal hypoplasia, and male aggressiveness and, for p27-/- mice, body weight, retinal hyperplasia, and embryo implantation. p27-/- traits that were not corrected were the aberrant estrus cycles, luteal cell proliferation, and susceptibility to pituitary tumors. This mutual correction of these phenotypes is the first genetic demonstration of the interaction of these inhibitory and stimulatory cell cycle-regulatory molecules in vivo. The molecular basis for the correction was analyzed in the neonatal retina. Retinal cellularity was rescued in the cyclin D1 null mouse by loss of p27 with only a partial restoration of phosphorylation of retinoblastoma protein (Rb) and Cdk4 activity but with a dramatic elevation of Cdk2 activity. Our data provide in vivo genetic validation of cell culture experiments that indicated that p27 acts as a negative regulator of cyclin E-Cdk2 activity and that it can be titrated away by cyclin D-Cdk4 complexes. It also supports the suggestion that the cyclin E/Cdk2 pathway can largely bypass Rb in regulating the cell cycle in vivo.

* Corresponding author. Mailing address: Center for the Study of Reproductive Biology and Women's Health, Departments of Developmental and Molecular Biology and Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Ave., New York, NY 10461. Phone: (718) 430-2090. Fax: (718) 430-8972. E-mail: pollard{at}aecom.yu.edu.

dagger Present address: Whitehead Institute, Massachusetts Institute of Technology, Cambridge, MA 02142.

Molecular and Cellular Biology, February 2001, p. 1319-1328, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1319-1328.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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