Interferon-alpha inhibits cell cycle progression by Ba/F3 cells through the antagonisation of interleukin-3 effects on key regulators of G(1)/S transition.
The molecular mechanisms of interferon-alpha (IFN-alpha)-mediated cell growth inhibition are incompletely understood. Here, we have analysed how IFN-alpha interferes with the interleukin-3 (IL-3)-stimulated cell cycle progression by Ba/F3 cells. The antiproliferative cytokine caused a delay in cell cycle progression, which correlated with a diminished activation of the cyclin-dependent kinases 2 and 4 in IL-3-stimulated cells. While IFN-alpha did not affect the expression of p27(Kip1) and p21(Waf1), it efficiently inhibited the IL-3-induced expression of D-type cyclin and cyclin E proteins. No IL-3-antagonistic effects of the IFN, however, were observed at the mRNA level of cyclin expression. Furthermore, IFN-alpha suppressed the IL-3-induced release of E2F transcription factors from the retinoblastoma protein (pRb) and enhanced pRb-mediated transcriptional repression. The growth factor-antagonistic action of IFN-alpha correlated with a strong stimulation of protein kinase R expression, suggesting that inhibition of protein synthesis plays a pivotal role in IFN-alpha-mediated inhibition of cell cycle progression.
Prietzsch
Holger
H
Institute of Medical Biochemistry and Molecular Biology, Medical Faculty, University of Rostock, Rostock, Germany.
Brock
Josef
J
Kleine
Hans-Dieter
HD
Liebe
Stefan
S
Jaster
Robert
R
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D016193:G1 Phase / Q000187:drug effects; D016898:Interferon-alpha / Q000494:pharmacology*; D007377:Interleukin-3 / Q000037:antagonists & inhibitors*; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors; D016196:S Phase; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016898:Interferon-alpha; D007377:Interleukin-3; D012333:RNA, Messenger; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019892:eIF-2 Kinase; D018844:Cyclin-Dependent Kinases