Aryl hydrocarbon receptor ligands repress T-cadherin expression in vascular smooth muscle cells

Niermann, Thomas; Schmutz, Sanja; Erné, Paul; Resink, Thérèse J.

doi:10.1016/s0006-291x(02)02970-4

Cited by 39 publications

(31 citation statements)

References 32 publications

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“…These data suggest that the AhR negatively regulate Ltbp-1 expression in MEF in the absence of xenobiotics, and therefore, underline the role of the AhR as a transcriptional repressor. Negative regulation of T-cadherin expression by the AhR has been previously suggested (Niermann et al, 2003). Thus, Ltbp-1 represents a new AhR-regulated gene not involved in xenobiotic metabolism.…”

Section: Discussionmentioning

confidence: 82%

“…Therefore, one of the important issues in order to define endogenous roles for the AhR is to identify its target genes under normal cellular conditions. In this context, recent work has found that p27 (Kolluri et al, 1999), Bax (Matikainen et al, 2001), T-cadherin (Niermann et al, 2003) and N-myristoyltranferase-2 (Kolluri et al, 2001) constitute novel target genes regulated through the AhR pathway.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, recent studies have shown that the AhR is involved in regulating the expression of constitutive proteins such as the DNA polymerase kappa (Ogi et al, 2001), Nmyristoyltransferase 2 (Kolluri et al, 2001), p27 Kip1 (Kolluri et al, 1999) and Bax (Matikainen et al, 2001). Interestingly, inhibitory regulatory elements (iDRE) have been also identified in estrogen responsive genes such as pS2 and cathepsin D (Safe et al, 1998), and in the T-cadherin promoter (Niermann et al, 2003). Thus, it appears plausible that the AhR could regulate the expression of genes involved in maintaining normal cell physiology.…”

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confidence: 99%

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Overexpression of latent transforming growth factor-β binding protein 1 (LTBP-1) in dioxin receptor-null mouse embryo fibroblasts

Santiago-Josefat

Mulero‐Navarro

Dallas

et al. 2004

Journal of Cell Science

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The aryl hydrocarbon receptor (AhR) is a transcriptional regulator of genes involved in xenobiotic metabolism. Increasingly clear is also the role of the AhR in the control of cell growth and proliferation. By analyzing differential patterns of gene expression between wild-type (AhR+/+) and null (AhR–/–) mouse embryo fibroblasts (MEF), we have identified latent transforming growth factor-β binding protein 1 (LTBP-1) as a negatively AhR-regulated gene in the absence of xenobiotics. Ltbp-1 mRNA and protein expression were markedly increased in AhR–/– MEF. Furthermore, secreted LTBP-1 was elevated in the culture medium and the extracellular matrix of AhR-null MEF. Actinomycin D inhibited Ltbp-1 mRNA overexpression, suggesting regulation at the transcriptional level. AhR activation by dioxin (TCDD) downregulated Ltbp-1, again suggesting an AhR-regulated mechanism. Treatment of AhR+/+ MEF with transforming growth factor-β(TGF-β) downregulated AhR and, simultaneously, increased Ltbp-1, further supporting the role of this receptor in LTBP-1 expression. AhR–/– conditioned medium had higher levels of active and total TGF-β activity, suggesting a role for LTBP-1 in maintaining extracellular TGF-β concentrations. TGF-β did not appear to directly regulate Ltbp-1 given that addition of TGFβ neutralizing antibody or TGFβ protein to AhR–/– MEF had no effect on Ltbp-1 expression. AhR–/– MEF had lower levels of matrix metalloproteinase 2 (MMP-2) activity, which could not be attributable to MMP-2 mRNA downregulation or MMP-inhibitors Timp-1 and Timp-2 overexpression. These data identify LTBP-1 as one of the few AhR-regulated genes not involved in xenobiotic metabolism and also support the implication of the AhR in controlling TGFβ activity and cell proliferation.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Overexpression of latent transforming growth factor-β binding protein 1 (LTBP-1) in dioxin receptor-null mouse embryo fibroblasts

Santiago-Josefat

Mulero‐Navarro

Dallas

et al. 2004

Journal of Cell Science

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“…Previous studies have suggested the involvement of the AhR in signaling pathways controlling cell migration and angiogenesis. Thus, this receptor is inhibited by the MEK antagonist PD98059 (61), AhR ligands inhibit Tcadherin expression in vascular endothelial cells (62) and disruption of cell-cell interactions activate the AhR in primary keratinocytes and 10T1/2 fibroblasts (63, 64). With respect to migration, T-FGM-AhRϪ/Ϫ cells had decreased migration in a collagen I matrix and in a tissue culture wound assay.…”

Section: Discussionmentioning

confidence: 99%

Immortalized Mouse Mammary Fibroblasts Lacking Dioxin Receptor Have Impaired Tumorigenicity in a Subcutaneous Mouse Xenograft Model

Mulero‐Navarro

Pozo‐Guisado

Pérez–Mancera

et al. 2005

Journal of Biological Chemistry

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Although the dioxin receptor, the aryl hydrocarbon receptor (AhR), is considered a major regulator of xenobiotic-induced carcinogenesis, its role in tumor formation in the absence of xenobiotics is still largely unknown. Trying to address this question, we have produced immortalized cell lines from wild-type (T-FGMAhR؉/؉) and mutant (T-FGM-AhR؊/؊) mouse mammary fibroblasts by stable co-transfection with the simian virus 40 (SV-40) large T antigen and proto-oncogenic c-HRas. Both cell lines had a myofibroblast phenotype and similar proliferation, doubling time, SV-40 and c-H-Ras expression and activity, and cell cycle distribution. AhR؉/؉ and AhR؊/؊ cells were also equally able to support growth factor-and anchorage-independent proliferation. However, the ability of T-FGM-AhR؊/؊ to induce subcutaneous tumors (leimyosarcomas) in NOD/ SCID-immunodeficient mice was close to 4-fold lower than T-FGM-AhR؉/؉. In culture, T-FGM-AhR؊/؊ had diminished migration in collagen-I and decreased lamellipodia formation. VEGFR-1/Flt-1, a VEGF receptor that regulates cell migration and blood vessel formation, was also down-regulated in AhR؊/؊ cells. Signaling through the ERK-FAK-PKB/AKT-Rac-1 pathway, which contributes to cell motility and invasion, was also significantly inhibited in T-FGM-AhR؊/؊. Thus, the lower tumorigenic potential of T-FGM-AhR؊/؊ could result from a compromised adaptability of these cells to the in vivo microenvironment, possibly because of an impaired ability to migrate and to respond to angiogenesis.

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“…32 In rat vascular smooth muscle cells, location of an AHR (aryl hydrocarbon)-responsive element (GCGTG) at À 45 bp was putatively correlated with AHR-ligand-dependent repression of CDH13. 33 Another study on vascular smooth muscle cells reported downmodulation of T-cadherin protein in response to growth factors such as platelet-derived growth factor, epidermal growth factor or insulin-like growth factor, but transcriptional mechanisms were not investigated. 34 In endothelial cells, a requirement of thioredoxin-1 in redox-sensitive modulation of T-cadherin expression was described and a thioredoxin-1-regulated region between À 156 and À 203 bp upstream of the translational start site of CDH13 was identified.…”

Section: Discussionmentioning

confidence: 99%

BRN2 is a transcriptional repressor of CDH13 (T-cadherin) in melanoma cells

Ellmann

Joshi

Resink

et al. 2012

Laboratory Investigation

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T-cadherin (cadherin 13, H-cadherin, gene name CDH13) has been proposed to act as a tumor-suppressor gene as its expression is significantly diminished in several types of carcinomas, including melanomas. Allelic loss and promoter hypermethylation have been proposed as mechanisms for silencing of CDH13. However, they do not account for loss of T-cadherin expression in all carcinomas, and other genetic or epigenetic alterations can be presumed. The present study investigated transcriptional regulation of CDH13 in melanoma. Bioinformatical analysis pointed to the presence of known BRN2 (also known as POU3F2 and N-Oct-3)-binding motifs in the CDH13 promoter sequence. We found an inverse correlation between BRN2 and T-cadherin protein and transcript expression. Reporter gene analysis and electrophoretic mobility shift assays in melanoma cells demonstrated that CDH13 is a direct target of BRN2 and that BRN2 is a functional transcriptional repressor of CDH13 promoter activity. The regulatory binding element of BRN2 was located À 219 bp of the CDH13 promoter proximal to the start codon and was identified as 5 0 -CATGCAAAA-3 0 . Ectopic expression of BRN2 in BRN2-negative/T-cadherin-positive melanoma cells resulted in suppression of CDH13 promoter activity, whereas BRN2 knockdown in BRN2-positive/T-cadherin-negative melanoma cells resulted in re-expression of T-cadherin transcripts and protein. Transcriptional repression of CDH13 by BRN2 may participate in malignant transformation of melanoma by increasing invasion and migration potentials of melanoma cells. The study has identified CDH13 as a novel direct BRN2 transcriptional target gene and has advanced knowledge of mechanisms underlying loss of T-cadherin expression in melanoma.

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Aryl hydrocarbon receptor ligands repress T-cadherin expression in vascular smooth muscle cells

Cited by 39 publications

References 32 publications

Overexpression of latent transforming growth factor-β binding protein 1 (LTBP-1) in dioxin receptor-null mouse embryo fibroblasts

Overexpression of latent transforming growth factor-β binding protein 1 (LTBP-1) in dioxin receptor-null mouse embryo fibroblasts

Immortalized Mouse Mammary Fibroblasts Lacking Dioxin Receptor Have Impaired Tumorigenicity in a Subcutaneous Mouse Xenograft Model

BRN2 is a transcriptional repressor of CDH13 (T-cadherin) in melanoma cells

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