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D-type cyclins (cyclins D1, D2, and D3) are regarded as essential links between cell environment and the core cell cycle machinery. We tested the requirement for D-cyclins in mouse development and in proliferation by generating mice lacking all D-cyclins. We found that these cyclin D1(-/-)D2(-/-)D3(-/-) mice develop until mid/late gestation and die due to heart abnormalities combined with a severe anemia. Our analyses revealed that the D-cyclins are critically required for the expansion of hematopoietic stem cells. In contrast, cyclin D-deficient fibroblasts proliferate nearly normally but show increased requirement for mitogenic stimulation in cell cycle re-entry. We found that the proliferation of cyclin D1(-/-)D2(-/-)D3(-/-) cells is resistant to the inhibition by p16(INK4a), but it critically depends on CDK2. Lastly, we found that cells lacking D-cyclins display reduced susceptibility to the oncogenic transformation. Our results reveal the presence of alternative mechanisms that allow cell cycle progression in a cyclin D-independent fashion.

Original publication

DOI

10.1016/j.cell.2004.07.025

Type

Journal article

Journal

Cell

Publication Date

20/08/2004

Volume

118

Pages

477 - 491

Keywords

Animals, Blotting, Northern, Blotting, Western, CDC2-CDC28 Kinases, Cell Cycle, Cell Division, Cell Transformation, Neoplastic, Cyclin A, Cyclin D1, Cyclin D2, Cyclin D3, Cyclin E, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase Inhibitor p16, Cyclins, Embryo, Mammalian, Fibroblasts, Flow Cytometry, Gene Expression Regulation, Developmental, Hematopoietic Stem Cells, Methylcellulose, Mice, Mice, Transgenic, Models, Biological, Phenotype, Protein Binding, Stem Cells, Time Factors