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Molecular and Cellular Biology, November 2006, p. 8052-8060, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00800-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Essential Role for Cyclin D3 in Granulocyte Colony-Stimulating Factor-Driven Expansion of Neutrophil Granulocytes

Ewa Sicinska,^1,2, Young-Mi Lee,^1,4, Judith Gits,³ Hirokazu Shigematsu,^4,5 Qunyan Yu,^1,4 Vivienne I. Rebel,⁶ Yan Geng,^1,4 Christopher J. Marshall,⁷ Koichi Akashi,^4,5 David M. Dorfman,^4,8 Ivo P. Touw,³ and Piotr Sicinski^1,4*

Department of Cancer Biology,¹ Center for Molecular Oncologic Pathology,² Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,⁴ Institute of Hematology, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands,³ Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139,⁵ Department of Cellular and Structural Biology, Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229,⁶ Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, London SW3 6JB, United Kingdom,⁷ Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115⁸

Received 5 May 2006/ Returned for modification 12 June 2006/ Accepted 15 August 2006

The proliferation of neutrophil granulocyte lineage is driven largely by granulocyte colony-stimulating factor (G-CSF) acting via the G-CSF receptors. In this study, we show that mice lacking cyclin D3, a component of the core cell cycle machinery, are refractory to stimulation by the G-CSF. Consequently, cyclin D3-null mice display deficient maturation of granulocytes in the bone marrow and have reduced levels of neutrophil granulocytes in their peripheral blood. The mutant mice are unable to mount a normal response to bacterial challenge and succumb to microbial infections. In contrast, the expansion of hematopoietic stem cells and lineage-committed myeloid progenitors proceeds relatively normally in mice lacking cyclin D3, revealing that the requirement for cyclin D3 function operates at later stages of neutrophil development. Importantly, we verified that this requirement is specific to cyclin D3, as mice lacking other G₁ cyclins (D1, D2, E1, or E2) display normal granulocyte counts. Our analyses revealed that in the bone marrow cells of wild-type mice, activation of the G-CSF receptor leads to upregulation of cyclin D3. Collectively, these results demonstrate that cyclin D3 is an essential cell cycle recipient of G-CSF signaling, and they provide a molecular link of how G-CSF-dependent signaling triggers cell proliferation.

Published ahead of print on 5 September 2006.

These authors contributed equally to this work.

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