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Dev Cell. 2014 Aug 11;30(3):255-67. doi: 10.1016/j.devcel.2014.06.015. Epub 2014 Jul 31.

D-cyclins repress apoptosis in hematopoietic cells by controlling death receptor Fas and its ligand FasL.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
2
Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
4
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
5
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
6
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: peter_sicinski@dfci.harvard.edu.

Abstract

D-type cyclins (D1, D2, and D3) are components of the mammalian core cell-cycle machinery and function to drive cell proliferation. Here, we report that D-cyclins perform a rate-limiting antiapoptotic function in vivo. We found that acute shutdown of all three D-cyclins in bone marrow of adult mice resulted in massive apoptosis of all hematopoietic cell types. We demonstrate that adult hematopoietic stem cells are particularly dependent on D-cyclins for survival and that they are especially sensitive to cyclin D loss. Surprisingly, we found that the antiapoptotic function of D-cyclins also operates in quiescent hematopoietic stem and progenitor cells. Our analyses revealed that D-cyclins repress the expression of the death receptor Fas and its ligand, FasL. Acute ablation of D-cyclins upregulated these proapoptotic genes and led to Fas- and caspase 8-dependent apoptosis. These results reveal an unexpected function of cell-cycle proteins in controlling apoptosis in normal cell homeostasis.

PMID:
25087893
PMCID:
PMC4134362
DOI:
10.1016/j.devcel.2014.06.015
[Indexed for MEDLINE]
Free PMC Article

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