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Volume 272, Number 16, Issue of April 18, 1997 pp. 10859-10869
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Elimination of Cyclin D1 in Vertebrate Cells Leads to an Altered Cell Cycle Phenotype, Which Is Rescued by Overexpression of Murine Cyclins D1, D2, or D3 but Not by a Mutant Cyclin D1

(Received for publication, November 21, 1996, and in revised form, January 23, 1997)

From the Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

DT40 lymphoma B-cells normally express cyclins D1 and D2 but not D3. When cyclin D1 expression was extinguished in these cells by gene knockout, specific alterations in their ability to transit the cell cycle were observed. These changes are exemplified by a delay of approximately 2 h in their progression through a normal 14-h cell cycle. This delay results in an increase in the number of cells in the G₂/M phase population, most likely due to triggering of checkpoints in G₂/M, inability to enter G₁ normally, and/or alterations of crucial event(s) in early G₁. The defect(s) in the cell cycle of these D1 "knockout" cells can be rescued by overexpression of any normal mouse D-type cyclin but not by a mutant mouse cyclin D1 protein that lacks the LXCXE motif at its amino terminus. These data suggest that the cell cycle alterations observed in the D1/ cells are a direct effect of the absence of the cyclin D1 protein and support the hypothesis that the D-type cyclins have separate, but overlapping, functions. Elimination of cyclin D1 also resulted in enhanced sensitivity to radiation, resulting in a significant increase in apoptotic cells. Expression of any normal murine D-type cyclin in the D1/ cells reversed this phenotype. Intriguingly, expression of the mutant cyclin D1 in the D1 / cells partially restored resistance to radiation-induced apoptosis. Thus, there may be distinct differences in cyclin D1 complexes and/or its target(s) in proliferating and apoptotic DT40 lymphoma B-cells.

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