Interferon-alpha-induced G1 phase arrest through up-regulated expression of CDK inhibitors, p19Ink4D and p21Cip1 in mouse macrophages

Oncogene. 1998 Apr 23;16(16):2075-86. doi: 10.1038/sj.onc.1201745.

Abstract

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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CDC2-CDC28 Kinases*
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins*
  • Cell Division / drug effects
  • Cell Line
  • Cyclin D1
  • Cyclin D2
  • Cyclin E
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p16*
  • Cyclin-Dependent Kinase Inhibitor p19
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / pharmacology
  • Cyclins / metabolism*
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Enzyme Inhibitors / metabolism*
  • G1 Phase
  • Interferon-alpha / metabolism*
  • Interferon-alpha / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice
  • Molecular Sequence Data
  • Protein Tyrosine Phosphatases / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins*
  • RNA, Messenger
  • S Phase
  • Time Factors
  • Up-Regulation*
  • cdc25 Phosphatases*

Substances

  • Carrier Proteins
  • Ccnd2 protein, mouse
  • Cdkn1a protein, mouse
  • Cdkn2d protein, mouse
  • Cell Cycle Proteins
  • Cyclin D2
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p19
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Interferon-alpha
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Cyclin D1
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • Cdk2 protein, mouse
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases
  • Cdc25a protein, mouse
  • Protein Tyrosine Phosphatases
  • cdc25 Phosphatases