Transcription factor GATA-6 activates expression of gastroprotective trefoil genes TFF1 and TFF2

Al-azzeh, Ezzal-din; Fegert, Petra; Blin, Nikolaus; Gött, Peter

doi:10.1016/s0167-4781(00)00013-0

Cited by 69 publications

(50 citation statements)

References 22 publications

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“…3A). The mutants serially eliminated consensus-binding sites of transcription factors that were known to alter TFF1 expression (7,16,20,21). Transient transfection of AGS gastric adenocarcinoma cells was followed by luciferase assays.…”

Section: Resultsmentioning

confidence: 99%

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Cofactor of BRCA1: A Novel Transcription Factor Regulator in Upper Gastrointestinal Adenocarcinomas

McChesney¹,

Aiyar²,

Lee

et al. 2006

Cancer Research

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Cofactor of BRCA1 (COBRA1) is a newly characterized member of the negative elongation factor (NELF) complex. In this work, we show that COBRA1 is overexpressed in the majority of primary upper gastrointestinal adenocarcinomas (UGC), and its overexpression correlates with down-regulation of TFF1. We have detected overexpression of COBRA1 mRNA using quantitative real-time reverse transcription-PCR in 28 (79%) primary UGCs. Immunohistochemical analysis of UGC tissue arrays that contained 70 tumor samples showed moderate-strong staining for COBRA1 in 60 (84%) tumors. Interestingly, the tumor samples showed absent-weak staining for TFF1 in 45 (65%) of the tumors. Simultaneous loss of TFF1 expression and overexpression of COBRA1 was observed in 42 of 70 (60%) tumors. Using small interfering RNA technology with gastric cancer cells, we have shown that COBRA1 inhibition leads to increased TFF1 promoter activity and gene expression. Promoter analysis of TFF1 indicated that regulation of TFF1 by COBRA1 is estrogen independent in contrast to breast cancer. Moreover, COBRA1 regulation of TFF1 in gastric cancer cells was independent of NELF-E. Using several truncated mutants and site mutants of the TFF1 promoter, we have shown that COBRA1 can negatively regulate the activator protein-1 (AP-1) complex at the TFF1 promoter and thus down-regulate TFF1 expression in gastric cancer cell lines. Electrophoretic mobility shift assay showed that COBRA1 attenuates AP-1 binding to DNA. Our results suggest COBRA1 as a novel oncogene in UGCs that regulate AP-1 binding and the expression of TFF1 in upper gastric epithelia.

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Section: Resultsmentioning

confidence: 99%

“…3A; refs. 7,[20][21][22]. As COBRA1 does not have a DNA-binding domain, it acts solely as a cofactor.…”

Section: Discussionmentioning

confidence: 99%

Cofactor of BRCA1: A Novel Transcription Factor Regulator in Upper Gastrointestinal Adenocarcinomas

McChesney¹,

Aiyar²,

Lee

et al. 2006

Cancer Research

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“…GATA binding sites occur within the regulatory regions of several gut epitheliumrestricted genes such as sucrase isomaltase, lactase-phlorizin hydrolase, liver-and intestine-type fatty acid binding proteins, sodium-hydrogen exchanger isoform 3, and trefoil factors 1 and 2. Furthermore, GATA4 activates these gut epitheliumrestricted genes in both gut epithelial and nonepithelial cells (2,13,20,22,27,31,33,39,40,45,64,73,79,80). Within the adult murine small intestine GATA4 is expressed in a gradient along the crypt-villus axis with strongest expression in differentiated enterocytes (13,22,28).…”

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confidence: 99%

Cooperation between GATA4 and TGF-β signaling regulates intestinal epithelial gene expression

Belaguli

Zhang²,

Rigi³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Members of the transforming growth factor-␤ (TGF-␤) family have been shown to play an important role in the regulation of gut epithelial gene expression. We have used the intestinal alkaline phosphatase (IAP) and intestinal fatty acid binding protein (IFABP) promoters to dissect the mechanisms by which TGF-␤1 signaling regulates gut epithelial gene expression. TGF-␤ signaling alone was not sufficient for activation of IAP and IFABP promoters. However, TGF-␤ signaling cooperated with the gut epithelial transcription factor GATA4 to synergistically activate IAP and IFABP promoters. Coexpression of GATA4 along with the TGF-␤1 signal transducing downstream effectors such as Smad2, 3, and 4 resulted in synergistic activation of both IAP and IFABP promoters. This synergistic activation was reduced by simultaneous expression of dominant-negative Smad4. Ϫ40 and Ϫ89 GATA binding sites in the IFABP promoter were required for the synergistic activation by Smad2, 3, and 4 and GATA4. GATA4 and Smad2, 3, and 4 physically associated with each other and this interaction was mediated through the MH2 domain of Smad2, 3, and 4 and the second zinc finger and the COOH-terminal basic domain of GATA4. The COOH-terminal activation domain and the Smad-interacting second zinc finger domain of GATA4 were required for the synergistic activation of the IFABP promoter. Naturally occurring oncogenic mutations within the GATA4-interacting MH2 domain of Smad2 reduced the coactivation of IFABP promoter by Smad2 and GATA4. Our results suggest that the TGF-␤ signaling regulates gut epithelial gene expression by targeting GATA4.

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“…Immunohistochemistry for murine GATA-4, GATA-5, and GATA-6 was performed as previously described (12). The normal small intestinal tissue samples were harvested from FVB/N mice on postnatal days 1,7,12,15,18, and 21. Briefly, tissues were fixed in 4% paraformaldehyde and embedded in paraffin before sectioning.…”

Section: Methodsmentioning

confidence: 99%

“…GATA-1, GATA-2, and GATA-3 are found in hematopoietic cells, whereas GATA-4, GATA-5, and GATA-6 are found in endodermic and mesodermic tissues, including the intestine. Numerous genes expressed in the intestinal epithelium are activated in cultured intestinal epithelial cell lines by GATA-4 (4,12,16,20,45), 16,20,27,30), and GATA-6 (1,16,18,20). We previously performed an immunohistochemical survey for GATA factors in the adult intestine and found that GATA-4 and GATA-6 are expressed in adult murine small intestinal enterocytes, with GATA-6 also present in crypt epithelial cells (12).…”

mentioning

confidence: 99%

Cooperative interactions among intestinal GATA factors in activating the rat liver fatty acid binding protein gene

Divine

Staloch²,

Haveri³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Transcription factor GATA-6 activates expression of gastroprotective trefoil genes TFF1 and TFF2

Cited by 69 publications

References 22 publications

Cofactor of BRCA1: A Novel Transcription Factor Regulator in Upper Gastrointestinal Adenocarcinomas

Cofactor of BRCA1: A Novel Transcription Factor Regulator in Upper Gastrointestinal Adenocarcinomas

Cooperation between GATA4 and TGF-β signaling regulates intestinal epithelial gene expression

Cooperative interactions among intestinal GATA factors in activating the rat liver fatty acid binding protein gene

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