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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Caspase 8 / metabolism
  • Cell Cycle / genetics
  • Cell Proliferation
  • Cyclin D1 / genetics
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Ligands
  • Mice
  • Mice, Knockout
  • fas Receptor / genetics
  • fas Receptor / metabolism*


  • Cyclins
  • Fas Ligand Protein
  • Ligands
  • fas Receptor
  • Cyclin D1
  • Casp8 protein, mouse
  • Caspase 8