Title

Mouse development and cell proliferation in the absence of D-cyclins.

Document Type

Article

Publication Date

2004

Keywords

Blotting-Western, CDC2-CDC28-Kinases, Cell-Cycle, Cell-Division, Cell-Transformation-Neoplastic, Cyclin-A, Cyclin-D1, Cyclin-E, Cyclins, Embryo, Fibroblasts, Flow-Cytometry, Gene-Expression-Regulation-Developmental, Hematopoietic-Stem-Cells, Methylcellulose, Mice, Mice-Transgenic, Models-Biological, Phenotype, Protein-Binding, Protein-p16, Research-Support-Non-U, S, -Gov't, Research-Support-U, S, -Gov't-P, H, S, Stem-Cells, Time-Factors

JAX Source

Cell 2004 Aug; 118(4):477-91.

Abstract

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.