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.
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Katarzyna
K
Kozar
Maria A
MA
Ciemerych
Vivienne I
VI
Rebel
Hirokazu
H
Shigematsu
Agnieszka
A
Zagozdzon
Ewa
E
Sicinska
Yan
Y
Geng
Qunyan
Q
Yu
Shoumo
S
Bhattacharya
Roderick T
RT
Bronson
Koichi
K
Akashi
Piotr
P
Sicinski
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D056742:Cyclin D2; D056743:Cyclin D3; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004622:Embryo, Mammalian / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000166:cytology; D008747:Methylcellulose / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010641:Phenotype; D011485:Protein Binding; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors
C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D019925:Cyclin A; D056742:Cyclin D2; D056743:Cyclin D3; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D019938:Cyclin D1; D008747:Methylcellulose; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2