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-1.
Highlights
The egr-1 gene, which is known as G0S30, NGFI-A, zif268, krox24, and Tis8, encodes a zincfinger-containing transcription factor and is an immediate-early response gene that is rapidly induced by stress, injury, mitogens, and differentiation factors in diverse cell types (Forsdyke, 1985; Sukhatme et al, 1988; Edwards et al, 1991; Liu et al, 1998)
To determine whether other protein synthesis inhibitor ANX activates egr-1 transcription, we examined the efficacy of CHX and ANX on Egr-1 expression in human U87MG glioma cells
We examined the effects of the translation inhibitors ANX and CHX on the activation of Egr-1 expression
Summary
The egr-1 gene, which is known as G0S30, NGFI-A, zif268, krox, and Tis, encodes a zincfinger-containing transcription factor and is an immediate-early response gene that is rapidly induced by stress, injury, mitogens, and differentiation factors in diverse cell types (Forsdyke, 1985; Sukhatme et al, 1988; Edwards et al, 1991; Liu et al, 1998). Expression of Egr-1 in several tumor cells is low (Huang et al, 1997), and the ectopic expression of egr-1 in tumor cells attenuates cell proliferation and tumorigenicity and increases cell attachment (de Belle et al, 1999; Liu et al, 1999; 2000) These results suggest that Egr-1 plays a key role in the regulation of cell growth and death in response to mitogens and stress signals. Extracellular growth factors such as EGF, FGF, and PDGF cause the rapid and transient transcriptional induction of egr-1. The TCFs represent a subfamily of Ets-domain transcription factors that contains at least three members, Elk-1 (Rao et al, 1989), Sap-1 (Dalton and Treisman, 1992), and Sap-2/Net/Erp (Dalton and Treisman, 1992; Lopez et al, 1994)
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