MEKK1 plays a critical role in activating the transcription factor C/EBP-beta-dependent gene expression in response to IFN-gamma.
IFN-gamma induces a number of genes to up-regulate cellular responses by using specific transcription factors and the cognate elements. We recently discovered that CCAAT/enhancer-binding protein-beta (C/EBP-beta) induces gene transcription through an IFN-response element called gamma-IFN-activated transcriptional element (GATE). Using mutant cells, chemical inhibitors, and specific dominant negative inhibitors, we show that induction of GATE-driven gene expression depends on MEK1 (mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase kinase) and ERKs (extracellular signal-regulated protein kinases) but is independent of Raf-1. Interestingly in cells lacking the MEKK1 gene or expressing the dominant negative MEKK1, ERK activation, and GATE dependent gene expression is inhibited. A dominant negative MEKK1 blocks C/EBP-beta-driven gene expression stimulated by IFN-gamma. These studies describe an IFN-gamma-stimulated pathway that involves MEKK1-MEK1-ERK1/2 kinases to regulate C/EBP-beta-dependent gene expression.
Roy
Sanjit K
SK
Department of Microbiology and Immunology, Molecular and Cellular Biology Program, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Hu
Junbo
J
Meng
Qingjun
Q
Xia
Ying
Y
Shapiro
Paul S
PS
Reddy
Sekhar P M
SP
Platanias
Leonidas C
LC
Lindner
Daniel J
DJ
Johnson
Peter F
PF
Pritchard
Catrin
C
Pagés
Gilles
G
Pouyssegur
Jacques
J
Kalvakolanu
Dhananjaya V
DV
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002460:Cell Line; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects*; D007371:Interferon-gamma / Q000494:pharmacology*; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
D022782:CCAAT-Enhancer-Binding Protein-beta; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse