A role for mixed lineage kinases in regulating transcription factor CCAAT/enhancer-binding protein-{beta}-dependent gene expression in response to interferon-{gamma}.
Transcription factor CCAAT/enhancer-binding protein-beta (C/EBP-beta) regulates a variety of cellular functions in response to exogenous stimuli. We have reported earlier that C/EBP-beta induces gene transcription through a novel interferon (IFN)-response element called gamma-IFN-activated transcriptional element. We show here that IFN-gamma-induced, C/EBP-beta/gamma-IFN-activated transcriptional element-dependent gene expression is regulated by mixed lineage kinases (MLKs), members of the mitogen-activated protein kinase kinase kinase family. MLK3 appears to activate C/EBP-beta in response to IFN-gamma by a mechanism involving decreased phosphorylation of a specific phosphoacceptor residue, Ser(64), within the transactivation domain. Decreased phosphorylation of Ser(64) was independent of IFN-gamma-stimulated ERK1/2 activation and did not require the ERK phosphorylation site Thr(189) located in regulatory domain 2 of C/EBP-beta. Together these studies provide the first evidence that MLK3 is involved in IFN-gamma signaling and identify a novel mechanism of transcriptional activation by IFN-gamma.
Roy
Sanjit K
SK
Greenebaum Cancer Center, Department of Microbiology and Immunology, University of Maryland School of Medicine, Balltimore, MD 21201, USA.
Shuman
Jon D
JD
Platanias
Leonidas C
LC
Shapiro
Paul S
PS
Reddy
Sekhar P M
SP
Johnson
Peter F
PF
Kalvakolanu
Dhananjaya V
DV
D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry* / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D022782:CCAAT-Enhancer-Binding Protein-beta; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma; D020930:MAP Kinase Kinase Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D034741:RNA, Small Interfering; D012694:Serine; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11