The translation inhibitor anisomycin induces Elk-1-mediated transcriptional activation of egr-1 through multiple mitogen-activated protein kinase pathways.
- Author:
Soon Young SHIN
1
;
Joon Ho LEE
;
Byung MIN
;
Young Han LEE
Author Information
1. Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Ansan 426-791, Korea. younghan@hanyang.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
anisomycin;
cycloheximide;
early growth response protein 1;
ets-domain protein Elk-1;
mitogen- activated protein kinases;
serum response element
- MeSH:
p38 Mitogen-Activated Protein Kinases/genetics/metabolism;
ets-Domain Protein Elk-1/genetics/*metabolism;
Trans-Activation (Genetics)/*drug effects;
Serum Response Element;
Protein Kinase Inhibitors/pharmacology;
Protein Biosynthesis/*drug effects;
Promoter Regions (Genetics)/genetics;
*MAP Kinase Signaling System/drug effects;
JNK Mitogen-Activated Protein Kinases/genetics/metabolism;
Humans;
Extracellular Signal-Regulated MAP Kinases/genetics/metabolism;
Early Growth Response Protein 1/genetics/*metabolism;
Cell Line, Tumor;
Anisomycin/*pharmacology
- From:Experimental & Molecular Medicine
2006;38(6):677-685
- CountryRepublic of Korea
- Language:English
-
Abstract:
The early growth response-1 gene (egr-1) encodes a zinc-finger transcription factor Egr-1 and is rapidly inducible by a variety of extracellular stimuli. Anisomycin (ANX), a protein synthesis inhibitor, stimulates mitogen-activated protein kinase (MAPK) pathways and thereby causes a rapid induction of immediate-early response genes. We found that anisomycin treatment of U87MG glioma cells resulted in a marked, time-dependent increase in levels of Egr-1 protein. The results of Northern blot analysis and reporter gene assay of egr-1 gene promoter (Pegr-1) activity indicate that the ANX- induced increase in Egr-1 occurs at the transcriptional level. Deletion of the serum response element (SRE) in the 5'-flanking region of egr-1 gene abolished ANX-induced Pegr-1 activity. ANX induced the phosphorylation of the ERK1/2, JNK, and p38 MAPKs in a time-dependent manner and also induced transactivation of Gal4-Elk-1, suggesting that Elk-1 is involved in SRE-mediated egr-1 transcription. Transient transfection of dominant-negative constructs of MAPK pathways blocked ANX-induced Pegr-1 activity. Furthermore, pretreatment with specific MAPK pathway inhibitors, including the MEK inhibitor U0126, the JNK inhibitor SP600125, and the p38 kinase inhibitor SB202190, completely inhibited ANX-inducible expression of Egr-1. Taken together, these results suggest that all three MAPK pathways play a crucial role in ANX-induced transcriptional activation of Pegr-1 through SRE-mediated transactivation of Elk
