title: Cyclin D- and E-dependent kinases and the p57(KIP2) inhibitor: cooperative interactions in vivo.
abstract: 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 p57(KIP2) 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 p57(KIP2) 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 p57(KIP2)-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 p57(KIP2) 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 p57(KIP2) to regulate the G1/S transition in a cell type highly dependent upon pRb.
authors.affiliation: Department of Microbiology and Immunology and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: E
authors.initials: E
authors.lastname: Gómez Lahoz
authors.forename: N J
authors.initials: NJ
authors.lastname: Liegeois
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.forename: J A
authors.initials: JA
authors.lastname: Engelman
authors.forename: J
authors.initials: J
authors.lastname: Horner
authors.forename: A
authors.initials: A
authors.lastname: Silverman
authors.forename: R
authors.initials: R
authors.lastname: Burde
authors.forename: M F
authors.initials: MF
authors.lastname: Roussel
authors.forename: C J
authors.initials: CJ
authors.lastname: Sherr
authors.forename: S J
authors.initials: SJ
authors.lastname: Elledge
authors.forename: R A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D042846:CDC2-CDC28 Kinases; D002467:Cell Nucleus / Q000378:metabolism; D003459:Crystallins; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D056742:Cyclin D2; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005260:Female; D016193:G1 Phase; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D016196:S Phase
chemical_list: C486196:Ccnd2 protein, mouse; C493965:Cdkn1c protein, mouse; D003459:Crystallins; D056742:Cyclin D2; D019927:Cyclin E; D050761:Cyclin-Dependent Kinase Inhibitor p57; D016213:Cyclins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; 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