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Research ArticleCELLULAR AND MOLECULAR

Transcriptional Regulation of Activating Transcription Factor 3 Involves the Early Growth Response-1 Gene

Frank G. Bottone Jr., Yuseok Moon, Brenda Alston-Mills and Thomas E. Eling
Journal of Pharmacology and Experimental Therapeutics November 2005, 315 (2) 668-677; DOI: https://doi.org/10.1124/jpet.105.089607
Frank G. Bottone Jr.
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Yuseok Moon
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Brenda Alston-Mills
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Thomas E. Eling
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Abstract

Previously, our laboratory identified activating transcription factor 3 (ATF3) as up-regulated by nonsteroidal anti-inflammatory drugs using microarray analysis of mRNA from human colorectal cancer cells treated with sulindac sulfide. ATF3 is a transcription factor involved in cell growth, apoptosis, and invasion and is induced by a variety of anticancer and dietary compounds. However, the regulation of ATF3 by anticancer agents is not known. The promoter of ATF3 contains several transcription factor binding sites. We identified three putative Egr-1 binding sites in the promoter of ATF3 and report for the first time that the molecular mechanism responsible for the transcriptional regulation of ATF3 by two divergent pharmaceutical compounds, sulindac sulfide and troglitazone, involved the early growth response gene-1 (Egr-1). For example, overexpression of Egr-1 protein induced ATF3 mRNA 3.5-fold and transcriptional activity of an ATF3 promoter construct more than 20-fold. ATF3 and Egr-1 mRNA and protein and ATF3 promoter activity were induced by these compounds, whereas induction of ATF3 by these compounds was blocked by Egr-1 small interfering RNA. Sulindac sulfide and troglitazone regulated ATF3 promoter activity, which was suppressed when the two Egr-1 sites were mutated. These compounds induced phosphorylation of extracellular signal-regulated kinase1/2 (Erk1/2), whereas a dominant-negative inhibitor of mitogen-activate protein kinase kinase (MEK) 1 blocked the induction of ATF3. The MEK1/2 inhibitor PD98059 (2′-amino-3′-methoxyflavone) blocked the induction of ATF3 and Egr-1 mRNA expression and ATF3 promoter activity by these compounds. Therefore, this is a novel first report demonstrating that the expression of ATF3 occurs via Egr-1 downstream of Erk1/2.

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  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.105.089607.

  • ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug(s); Cox, cyclooxygenase; ATF3, activating transcription factor 3; MEKK, mitogen-activated protein kinase kinase kinase; MAPK, mitogen-activated protein kinase; Erk, extracellular signal-regulated kinase; MG132, N-benzoy-loxycarbonyl (Z)-Leu-Leu-leucinal; NAG-1, nonsteroidal anti-inflammatory drug-activated gene-1; PPARγ, peroxisome proliferator-activated receptor-γ; Egr-1, early growth response gene-1; HCT, human colorectal; PD98059, 2′-amino-3′-methoxyflavone; SFM, serum-free media; PBS, phosphate-buffered saline; MEK, mitogen-activated protein kinase kinase; siRNA, small interfering RNA; RT-PCR, reverse transcription-polymerase chain reaction; bp, base pair(s); TBT-T, Tris-buffered saline/Tween 20; p-Erk, phosphoextracellular signal-regulated kinase; ANOVA, analysis of variance; CHX, cycloheximide; SC-560, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; SC-58125, 5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole.

    • Received May 19, 2005.
    • Accepted July 28, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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Research ArticleCELLULAR AND MOLECULAR

Transcriptional Regulation of Activating Transcription Factor 3 Involves the Early Growth Response-1 Gene

Frank G. Bottone, Yuseok Moon, Brenda Alston-Mills and Thomas E. Eling
Journal of Pharmacology and Experimental Therapeutics November 1, 2005, 315 (2) 668-677; DOI: https://doi.org/10.1124/jpet.105.089607

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Research ArticleCELLULAR AND MOLECULAR

Transcriptional Regulation of Activating Transcription Factor 3 Involves the Early Growth Response-1 Gene

Frank G. Bottone, Yuseok Moon, Brenda Alston-Mills and Thomas E. Eling
Journal of Pharmacology and Experimental Therapeutics November 1, 2005, 315 (2) 668-677; DOI: https://doi.org/10.1124/jpet.105.089607
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