Interferon-alpha-induced G1 phase arrest through up-regulated expression of CDK inhibitors, p19Ink4D and p21Cip1 in mouse macrophages.
The mechanism of cell cycle arrest induced by interferon-alpha (IFN-alpha) was analysed using a mouse macrophage cell line, BAC1.2F5A. IFN-alpha added in media before mid-G1 prohibited cells from entering S phase. The blockage of G1/S transition was associated with diminuition of both cyclin D1/cdk4- and cyclin E/cdk2-associated kinase activities. G1 cyclin-associated kinase activities were down-regulated quickly after the addition of IFN-alpha. Cells treated with IFN-alpha contained excess amounts of cdk inhibitors which down-regulated G1 cyclin/cdk-associated kinase activities in the proliferating cells and this action was counteracted by exogenously-supplied recombinant cyclin D2/cdk4 complexes. In parallel, accumulation of p19Ink4D and p21Cip1, and their attachment to cdks were up-regulated quickly after the addition of IFN-alpha. Expression of p19Ink4D and p21Cip1 was potentiated transcriptionally. We concluded that increased attachment of up-regulated cdk inhibitors including p19Ink4D and p21Cip1 to G1 cyclin/cdk complexes contributed to diminuition of G1 cyclin/cdk-associated kinase activities and resulting G1 phase arrest during the early phase of treatment with IFN-alpha.
Matsuoka
M
M
Department of Hematology and Oncology, Institute of Medical Science, University of Tokyo, Japan.
Tani
K
K
Asano
S
S
D000595:Amino Acid Sequence; D000818:Animals; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D019938:Cyclin D1; D056742:Cyclin D2; D019927:Cyclin E; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016213:Cyclins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000378:metabolism*; D016193:G1 Phase; D016898:Interferon-alpha / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016196:S Phase; D013997:Time Factors; D015854:Up-Regulation; D020687:cdc25 Phosphatases
D002352:Carrier Proteins; C486196:Ccnd2 protein, mouse; C493957:Cdkn1a protein, mouse; C493975:Cdkn2d protein, mouse; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; C517005:Cdc25a protein, mouse; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases