Mouse Development and Cell Proliferation in the Absence of D-Cyclins
Copyright policy )Mouse Development and Cell Proliferation in the Absence of D-Cyclins
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.
- Brigham and Women's Faulkner Hospital United States
- Harvard University United States
- Jackson Laboratory United States
- University of Warsaw Poland
- Tufts University United States
Hematopoietic-Stem-Cells, Research-Support-Non-U, Stem-Cells, -Gov't-P, Blotting-Western, Gene-Expression-Regulation-Developmental, Mice, Research-Support-U, Models-Biological, CDC2-CDC28 Kinases, Cyclin D2, Cyclin D1, Cyclin D3, Cyclin-E, S, Cyclin-A, Cell Cycle, Cell-Transformation-Neoplastic, Gene Expression Regulation, Developmental, Flow Cytometry, Phenotype, Cell Transformation, Neoplastic, Embryo, Cell-Division, Cell Division, Cell-Cycle, Blotting, Western, 610, Cyclin A, Methylcellulose, Mice-Transgenic, H, CDC2-CDC28-Kinases, Cyclin-D1, Cyclins, Cyclin E, Animals, Cyclin-Dependent Kinase Inhibitor p16, Biochemistry, Genetics and Molecular Biology(all), Cyclin-Dependent Kinase 2, -Gov't, Time-Factors, Fibroblasts, Blotting, Northern, Embryo, Mammalian, Hematopoietic Stem Cells, Flow-Cytometry, Protein-Binding, Protein-p16
Hematopoietic-Stem-Cells, Research-Support-Non-U, Stem-Cells, -Gov't-P, Blotting-Western, Gene-Expression-Regulation-Developmental, Mice, Research-Support-U, Models-Biological, CDC2-CDC28 Kinases, Cyclin D2, Cyclin D1, Cyclin D3, Cyclin-E, S, Cyclin-A, Cell Cycle, Cell-Transformation-Neoplastic, Gene Expression Regulation, Developmental, Flow Cytometry, Phenotype, Cell Transformation, Neoplastic, Embryo, Cell-Division, Cell Division, Cell-Cycle, Blotting, Western, 610, Cyclin A, Methylcellulose, Mice-Transgenic, H, CDC2-CDC28-Kinases, Cyclin-D1, Cyclins, Cyclin E, Animals, Cyclin-Dependent Kinase Inhibitor p16, Biochemistry, Genetics and Molecular Biology(all), Cyclin-Dependent Kinase 2, -Gov't, Time-Factors, Fibroblasts, Blotting, Northern, Embryo, Mammalian, Hematopoietic Stem Cells, Flow-Cytometry, Protein-Binding, Protein-p16
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