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

Katarzyna Kozar, Maria A. Ciemerych, Vivienne I. Rebel, Hirokazu Shigematsu, Agnieszka Zagozdzon, Ewa Sicinska, Yan Geng, Qunyan Yu, Shoumo Bhattacharya, Roderick T. Bronson, Koichi Akashi, Piotr Sicinski

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488 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)477-491
Number of pages15
JournalCell
Volume118
Issue number4
DOIs
StatePublished - Aug 20 2004

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kozar, K., Ciemerych, M. A., Rebel, V. I., Shigematsu, H., Zagozdzon, A., Sicinska, E., Geng, Y., Yu, Q., Bhattacharya, S., Bronson, R. T., Akashi, K., & Sicinski, P. (2004). Mouse development and cell proliferation in the absence of D-cyclins. Cell, 118(4), 477-491. https://doi.org/10.1016/j.cell.2004.07.025