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PMID: 12048245 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

MEKK1 plays a critical role in activating the transcription factor C/EBP-beta-dependent gene expression in response to IFN-gamma.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 12 ·2002-06-11 ·Pages 7945-50

Roy SK, Hu J, Meng Q, Xia Y, Shapiro PS, Reddy SP, Platanias LC, Lindner DJ, Johnson PF, Pritchard C, Pagés G, Pouyssegur J, Kalvakolanu DV

Abstract

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.

MeSH Terms
Animals CCAAT-Enhancer-Binding Protein-beta/metabolism Cell Line Gene Deletion Gene Expression Regulation/drug effects Interferon-gamma/pharmacology MAP Kinase Kinase Kinase 1 MAP Kinase Signaling System/physiology Macrophages Mice Mitogen-Activated Protein Kinases/metabolism Mutagenesis, Site-Directed Protein Serine-Threonine Kinases/metabolism Transcription, Genetic/drug effects Transcriptional Activation
Chemicals
CCAAT-Enhancer-Binding Protein-beta Interferon-gamma Protein Serine-Threonine Kinases Mitogen-Activated Protein Kinases MAP Kinase Kinase Kinase 1 Map3k1 protein, mouse
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Roy Sanjit K
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
Meng Qingjun
Xia Ying
Shapiro Paul S
Reddy Sekhar P M
Platanias Leonidas C
Lindner Daniel J
Johnson Peter F
Pritchard Catrin
Pagés Gilles
Pouyssegur Jacques
Kalvakolanu Dhananjaya V
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.122075799
Published
2002-06-11
Epub
2002-00-04
Pages
7945-50
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC123000
Subset
IM
Grants
NCI NIH HHS · CA 77816 · United States
NHLBI NIH HHS · R01 HL058122 · United States
NCI NIH HHS · R01 CA077816 · United States
NCI NIH HHS · CA 78282 · United States
NHLBI NIH HHS · R29 HL058122 · United States
NCI NIH HHS · R01 CA078282 · United States
NCI NIH HHS · CA 71401 · United States
NHLBI NIH HHS · HL 58122 · United States
NCI NIH HHS · CA 73881 · United States
External Links
PubMed source DOI: 10.1073/pnas.122075799 PMC Full Text View journal details
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