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Molecular and Cellular Biology, January 1999, p. 353-363, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cyclin D- and E-Dependent Kinases and the p57KIP2 Inhibitor: Cooperative Interactions In Vivo

Enrique Gómez Lahoz,1,dagger Nanette J. Liegeois,1 Pumin Zhang,2 Jeffrey A. Engelman,1 James Horner,1 Adam Silverman,1 Ronald Burde,1 Martine F. Roussel,3 Charles J. Sherr,3,4 Stephen J. Elledge,2,5 and Ronald A. DePinho1,*

Department of Microbiology and Immunology and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461;1 Howard Hughes Medical Institute4 and Department of Tumor Cell Biology,3 St. Jude Children's Research Hospital, Memphis, Tennessee 38105; and Verna & Marrs McLean Department of Biochemistry2 and Howard Hughes Medical Institute and Department of Molecular and Human Genetics,5 Baylor College of Medicine, Houston, Texas 77030

Received 9 December 1997/Returned for modification 12 January 1998/Accepted 28 September 1998

This study examines in vivo the role and functional interrelationships of components regulating exit from the G1 resting phase into the DNA synthetic (S) phase of the cell cycle. Our approach made use of several key experimental attributes of the developing mouse lens, namely its strong dependence on pRb in maintenance of the postmitotic state, the down-regulation of cyclins D and E and up-regulation of the p57KIP2 inhibitor in the postmitotic lens fiber cell compartment, and the ability to target transgene expression to this compartment. These attributes provide an ideal in vivo context in which to examine the consequences of forced cyclin expression and/or of loss of p57KIP2 inhibitor function in a cellular compartment that permits an accurate quantitation of cellular proliferation and apoptosis rates in situ. Here, we demonstrate that, despite substantial overlap in cyclin transgene expression levels, D-type and E cyclins exhibited clear functional differences in promoting entry into S phase. In general, forced expression of the D-type cyclins was more efficient than cyclin E in driving lens fiber cells into S phase. In the case of cyclins D1 and D2, ectopic proliferation required their enhanced nuclear localization through CDK4 coexpression. High nuclear levels of cyclin E and CDK2, while not sufficient to promote efficient exit from G1, did act synergistically with ectopic cyclin D/CDK4. The functional differences between D-type and E cyclins was most evident in the p57KIP2-deficient lens wherein cyclin D overexpression induced a rate of proliferation equivalent to that of the pRb null lens, while overexpression of cyclin E did not increase the rate of proliferation over that induced by the loss of p57KIP2 function. These in vivo analyses provide strong biological support for the prevailing view that the antecedent actions of cyclin D/CDK4 act cooperatively with cyclin E/CDK2 and antagonistically with p57KIP2 to regulate the G1/S transition in a cell type highly dependent upon pRb.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St. M463, Boston, MA 02115. Phone: (617) 632-6085. Fax: (617) 632-6069. E-mail: ron_depinho{at}dfci.harvard.edu.

dagger Present address: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

Molecular and Cellular Biology, January 1999, p. 353-363, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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