Inhibition of granulocyte differentiation by G1 cyclins D2 and D3 but not D1.
Growth factor-induced signals govern the expression of three D-type cyclins, which, in turn, function as regulatory subunits of cyclin-dependent kinases (cdks) to control cell cycle transitions during the late G1 interval. 32D myeloid cells, which self-renew as uncommitted precursors in interleukin 3 (IL-3), express cyclins D2 and D3 (but not D1) in complexes with cdk4 and cdk2. When transferred to granulocyte colony-stimulating factor (G-CSF), 32D cells stop dividing and terminally differentiate to mature neutrophils. Cyclin D and cdk4 expression ceased as cells underwent growth arrest in G-CSF, but cdk2 levels were sustained. 32D cells engineered to ectopically express D-type cyclins exhibited contracted G1 intervals with a compensatory lengthening of S phase but remained IL-3 dependent for cell growth; those overexpressing cyclins D2 and D3 (but not D1) were unable to differentiate and died in G-CSF. Cyclin D2 mutants, which cannot efficiently bind to, or functionally interact with, the retinoblastoma protein (pRb) or its relatives (p107) did not block differentiation. Conversely, the introduction of a catalytically inactive cdk4 mutant into cells overexpressing cyclin D2 restored their G-CSF response. The persistence of cdk2 and its predilection to functionally interact with cyclins D2 and D3 rather than D1 might explain the specificity of the differentiation blockade.
Kato
J Y
JY
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Sherr
C J
CJ
D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002999:Clone Cells; D019938:Cyclin D1; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins / Q000096:biosynthesis / Q000502:physiology*; D016193:G1 Phase; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology*; D006098:Granulocytes / Q000166:cytology* / Q000502:physiology; D008322:Mammals; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000502:physiology; D014162:Transfection
C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D015513:Oncogene Proteins; D011994:Recombinant Proteins; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D016179:Granulocyte Colony-Stimulating Factor; D011494:Protein Kinases