Accelerated entry into S phase associated with up-regulation of cyclin D1 as a mechanism for granulocyte colony-stimulating factor (G-CSF)-induced apoptosis of murine myeloid leukemia cells.
We previously reported that injection of recombinant granulocyte colony-stimulating factor (G-CSF) suppressed the development of leukemia in mice transplanted with C2M-A5 (C2M) myeloid leukemia cells and that the anti-leukemic effect of G-CSF was ascribed to the induction of apoptosis of C2M cells. These observations make a striking contrast with other previous reports on the biological activities of G-CSF. In the present study, in order to further clarify the G-CSF-induced apoptosis of C2M cells, we studied the effects of G-CSF on the cell cycle as well as the molecular events involving D-type cyclines and their cyclin-dependent kinases (cdk) in G-CSF-treated C2M cells. Cell cycle analysis revealed that G-CSF treatment of C2M cells resulted in accelerated entry from the first gap (G1) phase into the DNA synthesis (S) phase. Western blotting disclosed that G-CSF treatment resulted in down-regulation of cyclin D2 and cdk2 and up-regulation of cyclin D1 and cdk4. The reciprocal relationship between the up-regulation of cyclin D1 and down-regulation of cyclin D2 was closely associated with accelerated entry into S phase and subsequent apoptosis of C2M cells. These results suggest that G-CSF-induced apoptosis of C2M cells might be ascribed to imbalanced cell cycle progression due to deregulated expression of D-type cyclins and their cdks.
Kohno
T
T
First Department of Internal Medicine, Saitama Medical School, Japan.
Yoshida
S
S
Bessho
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016466:CHO Cells / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000502:physiology; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D016196:S Phase / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D019938:Cyclin D1; D016179:Granulocyte Colony-Stimulating Factor; D018844:Cyclin-Dependent Kinases