Disruption of cell?cell contact maximally but transiently activates AhR-mediated transcription in 10T1/2 fibroblasts*1

Cho, Young C.; Zheng, Weiguang; Jefcoate, Colin R.

doi:10.1016/j.taap.2003.12.025

Cited by 58 publications

(43 citation statements)

References 75 publications

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“…Second, AhR appears to be associated to and to co-localize with E-Cad and ␤-Cat in the periphery of NMuMG cells, indicating that AhR deficiency could enhance EMT-dependent cell migration through altered cell-cell adhesion. In agreement with these results, early studies showed that AhR becomes induced in 10T1/2 fibroblasts after de-assembling of cell-cell contacts (53). Finally, the increased migration of AhR knockdown cells is consistent with the more efficient wound healing found in AhRnull mice due to increased keratinocyte migration (10).…”

Section: Discussionsupporting

confidence: 76%

Dioxin Receptor Expression Inhibits Basal and Transforming Growth Factor β-induced Epithelial-to-mesenchymal Transition

Rico-Leo

Alvarez-Barrientos

Fernandez-Salguero

2013

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 76%

Dioxin Receptor Expression Inhibits Basal and Transforming Growth Factor β-induced Epithelial-to-mesenchymal Transition

Rico-Leo

Alvarez-Barrientos

Fernandez-Salguero

2013

Journal of Biological Chemistry

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“…Cell-cell contact has been shown to regulate gene expression in several cell types (2,6,9). More recently, Hwang et al (10) showed that microRNA expression was globally activated by cell-cell contact, using cell culture approaches very similar to those that we have taken to isolate the effects of cell-cell contact.…”

Section: Discussionmentioning

confidence: 96%

Cell-cell contact regulates gene expression in CDK4-transformed mouse podocytes

Sakairi

Abe

Jat

et al. 2010

American Journal of Physiology-Renal Physiology

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We transformed mouse podocytes by ectopic expression of cyclin-dependent kinase 4 (CDK4). Compared with podocytes transformed with a thermo-sensitive SV40 large T antigen mutant tsA58U19 (tsT podocytes), podocytes transformed with CDK4 (CDK4 podocytes) exhibited significantly higher expression of nephrin mRNA. Synaptopodin mRNA expression was significantly lower in CDK4 podocytes and in tsT podocytes under growth-permissive conditions (33°C) compared with tsT podocytes under growth-restricted conditions (37°C), which suggests a role for cell cycle arrest in synaptopodin mRNA expression. Confluent CDK4 podocytes showed significantly higher mRNA expression levels for nephrin, synaptopodin, Wilms tumor 1, podocalyxin, and P-cadherin compared with subconfluent cultures. We carried out experiments to clarify roles of various factors in the confluent podocyte cultures; our findings indicate that cell-cell contact promotes expression of five podocyte marker genes studied, that cellular quiescence increases synaptopodin and podocalyxin mRNA expression, and that soluble factors play a role in nephrin mRNA expression. Our findings suggest that CDK4 podocytes are useful tools to study podocyte biology. Furthermore, the role of cell-cell contact in podocyte gene expression may have relevance for podocyte function in vivo.cyclin-dependent kinase 4; SV40 large T antigen; nephrin; synaptopodin; Wilms tumor-1; P-cadherin PODOCYTE CULTURES, ESPECIALLY podocyte cell lines transformed by thermosensitive SV40 large T antigen (SV40 T), have been widely used to study podocyte biology (19,25). However, as we recently reported in studies on a generation of mouse and human podocyte cell lines, podocytes transformed by thermosensitive SV40 T (tsT) exhibit phenotypic differences compared with podocytes in vivo, with reduced expression of certain differentiation marker genes (13, 24).Cyclin-dependent kinase 4 (CDK4), a catalytic subunit of the cyclin D-CDK4 serine/threonine kinase complex, is a critical regulator of the cell cycle. CDK4 is the first kinase activated by mitogenic signals. The kinase activity of CDK4 is specifically involved in progression through G1, via phosphorylation of retinoblastoma (Rb) family members (4). Recently, Ramirez et al. (22) immortalized human bronchial epithelial cells by ectopic expression of CDK4 and human telomerase (hTERT). Microarray analysis showed that CDK4/hTERTimmortalized cells showed significantly different gene expression profiles compared with cells immortalized with human papiloma viral oncoproteins E6/E7 or SV40T and that CDK4-transformed cells clustered with primary bronchial epithelial cells. In addition, recent studies showed that cells immortalized with CDK4 are useful tools to study physiology and pathophysiology (8,23,30).We set out to develop an alternative approach to transforming podocytes by comparing the phenotype among primary cells, CDK4-transformed podocytes (CDK4-podocytes) and thermosensitive SV40 T mutant tsA58U19 (tsT-podocytes). We found that CDK4-podocytes and tsT-podocyt...

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“…Moreover, AhR localization may be regulated depending on the density of murine fibroblasts or human keratinocytes. Here, sparse density favored nuclear AhR localization whereas AhR was found predominantly in the cytoplasm at confluence (27,28). We noticed a reduction in AhR signaling upon integrin inhibition that was not restricted to the adherent cell fraction, but was observed in the floating cell fraction to a similar extent (Fig.…”

Section: Discussionmentioning

confidence: 53%

The aryl hydrocarbon receptor links integrin signaling to the TGF-β pathway

et al. 2015

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Glioblastoma is the most common and aggressive form of intrinsic brain tumor. Transforming growth factor (TGF)-represents a central mediator of the malignant phenotype of these tumors by promoting invasiveness and angiogenesis, maintaining tumor cell stemness and inducing profound immunosuppression. Integrins, which are highly expressed in glioma cells, interact with the TGF-pathway. Furthermore, a link has been described between activity of the transcription factor aryl hydrocarbon receptor (AhR) and TGF-expression. Here we demonstrate that integrin inhibition, using v, 3 or 5 neutralizing antibodies, RNA interference-mediated integrin gene silencing or pharmacological inhibition by the cyclic RGD peptide EMD 121974 (cilengitide) or the non-peptidic molecule GLPG0187, inhibits AhR activity. These effects are independent of cell detachment or cell density. While AhR mRNA expression was not affected by integrin inhibition, AhR total and nuclear protein levels were reduced, suggesting that integrin inhibition-mediated regulation of AhR may occur at a post-transcriptional level. AhR-null astrocytes, AhR-null hepatocytes or glioblastoma cells with a transiently silenced AhR gene showed reduced sensitivity to integrin inhibition-mediated alterations in TGF-signaling, indicating that AhR mediates integrin control of the TGF-pathway. Accordingly, there was a significant correlation of v integrin levels with nuclear AhR and pSmad2 levels as determined by immunohistochemistry in human glioblastoma in vivo. In summary, this study identifies a signaling network comprising integrins, AhR and TGF-and validates integrin inhibition as a promising strategy not only to inhibit angiogenesis, but also to block AhR-and TGF--controlled features of malignancy in human glioblastoma. Here we demonstrate that integrin inhibition, using αv, β3 or β5 neutralizing antibodies, RNA interference-mediated integrin gene silencing or pharmacological inhibition by the cyclic RGD peptide EMD 121974 (cilengitide) or the non-peptidic molecule GLPG0187, inhibits AhR activity.These effects are independent of cell detachment or cell density. While AhR mRNA expression was not affected by integrin inhibition, AhR total and nuclear protein levels were reduced, suggesting that integrin inhibition-mediated regulation of AhR may occur at a posttranscriptional level. AhR-null astrocytes, AhR-null hepatocytes, or glioblastoma cells with a transiently silenced AhR gene showed reduced sensitivity to integrin inhibition-mediated alterations in TGF-β signaling indicating that AhR mediates integrin control of the TGF-β pathway. Accordingly, there was a significant correlation of αv integrin levels with nuclear AhR and pSmad2 levels as determined by immunohistochemistry in human glioblastoma in vivo.In summary, this study identifies a signaling network comprising integrins, AhR and TGF-β and validates integrin inhibition as a promising strategy not only to inhibit angiogenesis, but also to block AhR-and TGF--controlled features of malignancy in human glio...

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Disruption of cell?cell contact maximally but transiently activates AhR-mediated transcription in 10T1/2 fibroblasts*1

Cited by 58 publications

References 75 publications

Dioxin Receptor Expression Inhibits Basal and Transforming Growth Factor β-induced Epithelial-to-mesenchymal Transition

Dioxin Receptor Expression Inhibits Basal and Transforming Growth Factor β-induced Epithelial-to-mesenchymal Transition

Cell-cell contact regulates gene expression in CDK4-transformed mouse podocytes

The aryl hydrocarbon receptor links integrin signaling to the TGF-β pathway

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