Mouse Development and Cell Proliferation in the Absence of D-cyclins

Cell. 2004 Aug 20;118(4):477-91. doi: 10.1016/j.cell.2004.07.025.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Ccnd2 protein, mouse
  • Ccnd3 protein, mouse
  • Cyclin A
  • Cyclin D2
  • Cyclin D3
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclins
  • Cyclin D1
  • Methylcellulose
  • CDC2-CDC28 Kinases
  • Cdk2 protein, mouse
  • Cyclin-Dependent Kinase 2