The gut-enriched Krüppel-like factor (GKLF) suppresses the promoter activity of the cytochrome P450 1A1 (CYP1A1) gene in a SP1-dependent fashion

Zhang, WQ; Shields, J.E.; Yang, VW

doi:10.1016/s0016-5085(98)83730-x

Cited by 5 publications

(8 citation statements)

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“…The rationale for examining KLF6 as a component of the NC-XRE-bound complex in the PAI-1 promoter was founded on several complementary observations: 1) sequence homology between the NC-XRE and the consensus binding site for KLF proteins, 2) prior evidence of a functional relationship between the AhR and a KLF family member in the brain and gut (Imataka et al, 1992;Zhang et al, 1998), 3) expression of KLF6 in the liver (Ratziu et al, 1998;Narla et al, 2007), 4) a role of KLF6 in cell proliferation reminiscent of the AhR's role in cell proliferation, and 5) increased nuclear localization of KLF6 resulting in enhanced PAI-1 expression (Gehrau et al, 2010). KLF6 binds to the GC-rich region or CACCC elements of the DNA sequence in the target gene promoter (Philipsen and Suske, 1999;Bieker, 2001) and regulates expression of a large number of genes involved in differentiation, proliferation, and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…The KLF family is a recently identified and growing superfamily of transcription factors related to specificity protein 1 (Sp1) and characterized by three zinc finger domains in their C termini that confer binding to a "GC-box" linked to diverse target genes (Philipsen and Suske, 1999;Bieker, 2001). Supporting a potential interaction between the AhR and a KLF family member, two separate KLF family members have been associated with the established AhR target gene CYP1A1: KLF9 can bind to regions in the rat CYP1A1 promoter and modulate its expression (Imataka et al, 1992), and KLF4 inhibits CYP1A1 induction via an interaction with Sp1 (Zhang et al, 1998). However, neither KLF9 nor KLF4 are expressed in the liver, the site of AhR-dependent PAI-1 induction involving the NC-XRE.…”

Section: Introductionmentioning

confidence: 99%

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The Tumor Suppressor Kruppel-Like Factor 6 Is a Novel Aryl Hydrocarbon Receptor DNA Binding Partner

Wilson

Joshi

Elferink³

2013

J Pharmacol Exp Ther

110

100

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The aryl hydrocarbon receptor (AhR) is a ligand-mediated basic helix-loop-helix transcription factor of the Per/Arnt/Sim family that regulates adaptive and toxic responses to a variety of chemical pollutants, including polycyclic aromatic hydrocarbons and halogenated aromatic hydrocarbons, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Ligand activation leads to AhR nuclear translocation and binding to a xenobiotic response element (XRE) in association with the Arnt to regulate gene expression. Several recent genome-wide transcriptional studies identified numerous AhR target genes that lack the canonical XRE recognition site in the promoter regions. Characterization of one such target gene, the plasminogen activator inhibitor 1, identified a novel nonconsensus XRE (NC-XRE) that confers TCDD responsiveness independently of the Arnt protein.Studies reported here show that the NC-XRE is a recognition site for the AhR and a new binding partner, the Kruppel-like factor (KLF) family member KLF6. In vivo chromatin immunoprecipitations and in vitro DNA binding studies demonstrate that the AhR and KLF6 proteins form an obligatory heterodimer necessary for NC-XRE binding. Mutational analyses show that the protein-protein interactions involve the AhR C terminus and KLF6 N terminus, respectively. Moreover, NC-XRE binding depends on the 59 basic region in KLF6 rather than the previously characterized zinc finger DNA binding domain. Collectively, the results unmask a novel AhR signaling mechanism distinct from the canonical XREdriven process that will enrich our future understanding of AhR biology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Tumor Suppressor Kruppel-Like Factor 6 Is a Novel Aryl Hydrocarbon Receptor DNA Binding Partner

Wilson

Joshi

Elferink³

2013

J Pharmacol Exp Ther

110

100

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“…Functionally, KLF4 up-regulates differentiation marker genes such as keratin 4 or intestine alkaline phosphotase (16,17), whereas KLF4 down-regulates positive cell cycle -regulatory genes such as cyclin D1 and ornithine decarboxylase (18,19). Interestingly, several reports have indicated that KLF4 represses the expression of several genes by competing with Sp1 (49,50). However, whether KLF4 is involved in Sp1 regulation and tumor development and progression in gastric cancer is unknown.…”

Section: Discussionmentioning

confidence: 99%

Loss of Krüppel-Like Factor 4 Expression Contributes to Sp1 Overexpression and Human Gastric Cancer Development and Progression

Kanai¹,

Wei²,

Li³

et al. 2006

Clinical Cancer Research

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Purpose: Increasing evidence indicates that the transcription factor, Sp1, regulates the expression of multiple genes involved in tumor development and progression.We have recently reported that Sp1overexpression is directly correlated with the angiogenic potential of and poor prognosis for human gastric cancer. However, the underlying mechanisms that result in Sp1overexpression remain unclear. Experimental Design:The expression of Sp1and Kru« ppel-like factor 4 (KLF4), a potential tumor suppressor gene, in gastric cancer tissue was analyzed by immunohistochemistry and Western blot analysis. Alterations of Sp1and KLF4 expression were achieved by gene transfer and verified by Northern andWestern blot analyses. Furthermore, Sp1promoter activity assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay were done to identify the KLF4 binding sites on the Sp1promoter. Results: Mutually exclusive expression of Sp1and KLF4 was evident in gastric cancer and noncancerous tissue. Specifically, strong Sp1 expression but loss of KLF4 expression was found in cancer tissue, whereas the adjacent noncancerous tissue showed negative Sp1 expression but strong KLF4 expression. Enforced KLF4 expression repressed Sp1 expression at the promoter activity, mRNA, and protein levels. Moreover, a region within the proximal Sp1 promoter was identified to have overlapping KLF4-and Sp1-binding sites, to which KLF4 and Sp1compete for binding. Sp1positively regulated its own promoter, whereas KLF4 did the opposite. Conclusions: Our data suggests that disruption of KLF4-mediated negative regulation contributes to the molecular events of Sp1 overexpression and to the development and progression of human gastric cancer.Although the incidence of gastric cancer declined in the west from the 1940s to the 1980s, it remains a major public health problem throughout the world (1). In Asia and parts of South America in particular, it is the most common epithelial malignancy and is a leading cause of cancer-related death. In fact, gastric cancer remains the fourth most frequently diagnosed malignancy worldwide and is the cause of 12% of all cancer-related deaths annually (1). Advances in the treatment of this disease are likely to come from a fuller understanding of its biology and behavior. Although various genetic and molecular alterations have been found to be associated with the malignant transformation of gastric cancer, they may represent only the pathogenesis of this disease, and they have not been identified as a specific sequence of changes leading to gastric carcinoma (2, 3). Therefore, the role and detailed mechanisms of genetic and epigenetic changes in gastric cancer development and progression remain unclear.Sp1 is a zinc finger transcription factor that is important to the transcription of many cellular and viral genes that contain GC boxes in their promoter. Additional transcription factors that are similar to Sp1 in their structural and transcriptional properties (Sp2, Sp3, and Sp4) have been cloned, th...

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“…KLF4 has been shown to bind CACCC sequences and GC-rich sequences in the promoter of i.e. KRT4, p21WAF1/CIP1 and CYP1A1 genes [16][17][18][19]. Interestingly, the E-cadherin promoter contains several CACCC sequences and a GC-rich region, located between the two ZEB2 binding sites.…”

Section: Introductionmentioning

confidence: 99%

Interplay between KLF4 and ZEB2/SIP1 in the regulation of E-cadherin expression

Koopmansch

Berx

Foidart

et al. 2013

Biochemical and Biophysical Research Communications

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a b s t r a c t E-cadherin expression is repressed by ZEB2/SIP1 while it is induced by KLF4. Independent data from the literature indicate that these two transcription factors could bind close to each other in the proximal region of the E-cadherin gene promoter. We have here explored a potential competition between ZEB2 and KLF4 for the binding to the E-cadherin promoter. We show an inverse correlation between ZEB2 expression levels and KLF4 recruitment on the E-cadherin promoter in three breast cancer cell lines and in A431/HA.ZEB2 cells in which ZEB2 expression is induced by doxycycline (DOX). We identified a region of the E-cadherin promoter bound by KLF4 which is necessary for the activation of the E-cadherin promoter activity after KLF4 overexpression. This region is localized between positions À28 and À10 and thus overlaps with one of the ZEB2 binding sites. Deleting the bipartite ZEB2 binding site results in increased KLF4 induced E-cadherin promoter activity. Taken together, our results suggest that E-cadherin expression in cancer cells is controlled by a balance between ZEB2 and KLF4 expression levels.

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The gut-enriched Krüppel-like factor (GKLF) suppresses the promoter activity of the cytochrome P450 1A1 (CYP1A1) gene in a SP1-dependent fashion

Cited by 5 publications

References 0 publications

The Tumor Suppressor Kruppel-Like Factor 6 Is a Novel Aryl Hydrocarbon Receptor DNA Binding Partner

The Tumor Suppressor Kruppel-Like Factor 6 Is a Novel Aryl Hydrocarbon Receptor DNA Binding Partner

Loss of Krüppel-Like Factor 4 Expression Contributes to Sp1 Overexpression and Human Gastric Cancer Development and Progression

Interplay between KLF4 and ZEB2/SIP1 in the regulation of E-cadherin expression

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