TY - JOUR
T1 - Mouse development and cell proliferation in the absence of D-cyclins
AU - Kozar, Katarzyna
AU - Ciemerych, Maria A.
AU - Rebel, Vivienne I.
AU - Shigematsu, Hirokazu
AU - Zagozdzon, Agnieszka
AU - Sicinska, Ewa
AU - Geng, Yan
AU - Yu, Qunyan
AU - Bhattacharya, Shoumo
AU - Bronson, Roderick T.
AU - Akashi, Koichi
AU - Sicinski, Piotr
N1 - Funding Information:
The authors thank R. Kaminski, L. Litowchick, J. DeCaprio, S. Mittnacht, M. Cohn, L. Zhang, L. Callahan, J. Schneider, S. Neubauer, K. Clarke, and the members of the Sicinski lab for help; P. Hinds for anti-cyclin G1 antibody; N. Dyson for the probes for E2F targets; A. Gudkov, S. Lowe, and M. Eilers for the DNp53, Ras, and Myc retroviral constructs; and M. Malumbres and M. Barbacid for communicating unpublished data. M.A.C. was supported by the Yamagiwa-Yoshida Memorial UICC International Cancer Study Grant. V.I.R. was supported by a grant from the Leukemia and Lymphoma Society. This work was supported by grants from the NIH (CA85296 and CA108420) to P.S.
PY - 2004/8/20
Y1 - 2004/8/20
N2 - 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 p16INK4a, 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.
AB - 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 p16INK4a, 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.
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U2 - 10.1016/j.cell.2004.07.025
DO - 10.1016/j.cell.2004.07.025
M3 - Article
C2 - 15315760
AN - SCOPUS:4444307411
SN - 0092-8674
VL - 118
SP - 477
EP - 491
JO - Cell
JF - Cell
IS - 4
ER -