Signaling via the AHR leads to enhanced usage of CD44v10 by murine fetal thymic emigrants: possible role for CD44 in emigration

Esser, Charlotte; Temchura, Vladimir; Majora, Marc; Hundeiker, Claudia; Schwärzler, Christoph; Günthert, Ursula

doi:10.1016/j.intimp.2004.03.006

Cited by 12 publications

(12 citation statements)

References 69 publications

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“…Moreover, it has been observed that AhR has a predominantly nuclear distribution in cells located at the migrating edge in wound healing experiments (Ikuta and Kawajiri, 2006). It was also reported that both the ligand-dependent and the constitutive activation of AhR in the immune system leads to enhanced migration of CD4 Ϫ CD8 Ϫ double-negative lymphocytes from the thymus (Esser et al, 2004;Temchura et al, 2005). Finally, a recent work has shown that either dioxin or a constitutively active form of the AhR induce morphological changes that affect the F-actin cytoskeleton, cellcell interactions, and the motility of breast tumor cells (Diry et al, 2006).…”

Section: Discussionmentioning

confidence: 95%

The Dioxin Receptor Regulates the Constitutive Expression of theVav3Proto-Oncogene and Modulates Cell Shape and Adhesion

Carvajal-González

Mulero‐Navarro

Román

et al. 2009

MBoC

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The dioxin receptor (AhR) modulates cell plasticity and migration, although the signaling involved remains unknown. Here, we report a mechanism that integrates AhR into these cytoskeleton-related functions. Immortalized and mouse embryonic fibroblasts lacking AhR (AhR؊/؊) had increased cell area due to spread cytoplasms that reverted to wild-type morphology upon AhR re-expression. The AhR-null phenotype included increased F-actin stress fibers, depolarized focal adhesions, and enhanced spreading and adhesion. The cytoskeleton alterations of AhR؊/؊ cells were due to downregulation of constitutive Vav3 expression, a guanosine diphosphate/guanosine triphosphate exchange factor for Rho/Rac GTPases and a novel transcriptional target of AhR. AhR was recruited to the vav3 promoter and maintained constitutive mRNA expression in a ligand-independent manner. Consistently, AhR؊/؊ fibroblasts had reduced Rac1 activity and increased activation of the RhoA/Rho kinase (Rock) pathway. Pharmacological inhibition of Rac1 shifted AhR؉/؉ fibroblasts to the null phenotype, whereas Rock inhibition changed AhR-null cells to the AhR؉/؉ morphology. Knockdown of vav3 transcripts by small interfering RNA induced cytoskeleton defects and changes in adhesion and spreading mimicking those of AhR-null cells. Moreover, vav3؊/؊ MEFs, as AhR؊/؊ mouse embryonic fibroblasts, had increased cell area and enhanced stress fibers. By modulating Vav3-dependent signaling, AhR could regulate cell shape, adhesion, and migration under physiological conditions and, perhaps, in certain pathological states.

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Section: Discussionmentioning

confidence: 95%

The Dioxin Receptor Regulates the Constitutive Expression of theVav3Proto-Oncogene and Modulates Cell Shape and Adhesion

Carvajal-González

Mulero‐Navarro

Román

et al. 2009

MBoC

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“…CD184/CXCR4 is critical during development for seeding of the BM with HSCs and mediates migration and quiescence throughout adulthood (Nie et al, 2008). CD44 is highly expressed in prothymocytes (CD4 low CD25 Ϫ c-kit ϩ ) of the BM, serving as a homing receptor for the thymus (Wu et al, 1993), and CD44 expression was found to be up-regulated in thymic emigrants exposed to TCDD (Esser et al, 2004). Thus, it is reasonable, if not expected, that functional alterations in HSCs after TCDD treatment would be a reflection of altered expression and/or function of cell surface proteins.…”

Section: Lskcd48mentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activation in Hematopoietic Stem/Progenitor Cells Alters Cell Function and Pathway-Specific Gene Modulation Reflecting Changes in Cellular Trafficking and Migration

Casado¹,

Singh²,

Gasiewicz³

2011

Mol Pharmacol

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The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the Per-ARNT-Sim family of proteins. These proteins sense molecules and stimuli from the cellular/tissue environment and initiate signaling cascades to elicit appropriate cellular responses. Recent literature reports suggest an important function of AhR in hematopoietic stem cell (HSC) biology. However, the molecular mechanisms by which AhR signaling regulates HSC functions are unknown. In previous studies, we and others reported that treatment of mice with the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) compromises the competitive reconstitution of bone marrow (BM) cells into irradiated host animals. Additional studies indicated a requirement for AhR in hematopoietic cells and not marrow microenvironment cells. In this study, we tested the hypothesis that TCDDmediated phenotypic and functional changes of HSCs are a result of changes in gene expression that disrupt stem cell numbers and/or their migration. TCDD treatment to mice increased the numbers of phenotypically defined HSCs in BM. These cells showed compromised migration to the BM in vivo and to the chemokine CXCL12 in vitro, as well as increased expression of the leukemia-associated receptors CD184 (CXCR4) and CD44. Gene expression profiles at 6 and 12 h after exposure were consistent with the phenotypic and functional changes observed. The expressions of Scin, Nqo1, Flnb, Mmp8, Ilf9, and Slamf7 were consistently altered. TCDD also disrupted expression of other genes involved in hematological system development and function including Fos, JunB, Egr1, Ptgs2 (Cox2), and Cxcl2. These data support a molecular mechanism for an AhR ligand to disrupt the homeostatic cell signaling of HSCs that may promote altered HSC function.

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“…CD44 is a cell-surface glycoprotein that has been found to be correlated to both estrogen receptor status (Durst et al, 2001;Sorbello et al, 2003) and AhR signaling (Esser et al, 2004). However, as expected, none of the measured expression profiles correlated with the 5F-203 GI 50 data vector.…”

Section: Cellular Sensitivity (Gimentioning

confidence: 59%

Differential Gene Expression as a Potential Classifier of 2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole-Sensitive and -Insensitive Cell Lines

Wallqvist

Connelly²,

Sausville³

et al. 2005

Mol Pharmacol

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2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole (5F-203) is a candidate antitumor agent empirically discovered with the aid of the National Cancer Institute (NCI) Anticancer Drug Screen. In an effort to determine whether basal expression of genes could be used to classify cell sensitivity to this agent, serial analysis of gene expression (SAGE) libraries were generated for three sensitive and two insensitive human tumor cell lines. When the SAGE tags expressed within these cell line libraries were compared and evaluated for differences, several genes seemed more highly expressed in 5F-203-sensitive cell lines than in the insensitive cell lines. Constitutive expressions of 15 genes identified by the analysis were then measured by quantitative reverse-transcription polymerase chain reaction in the 60 cell lines of the NCI Anticancer Drug Screen. This generated a pattern of relative basal gene expression across the cell lines and also confirmed the differential expression of SAGE-discovered genes within the initial set of five cell lines. Further analyses of these expression data in 60 cell lines suggested that a smaller subset of genes could be used to classify tumor cell sensitivity to 5F-203. In contrast, the same set of genes did not predict with equivalent precision sensitivity to unrelated active drugs, and another set of genes could not better classify the cell lines in terms of 5F-203 sensitivity. These results suggest that constitutive gene expression profiles, in which the genes are not necessarily known to be related to the mechanism of action of a given drug, may be viewed as a general tool to extend and improve the concept of a single predictive gene to groups of predictive genes.

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Signaling via the AHR leads to enhanced usage of CD44v10 by murine fetal thymic emigrants: possible role for CD44 in emigration

Cited by 12 publications

References 69 publications

The Dioxin Receptor Regulates the Constitutive Expression of theVav3Proto-Oncogene and Modulates Cell Shape and Adhesion

The Dioxin Receptor Regulates the Constitutive Expression of theVav3Proto-Oncogene and Modulates Cell Shape and Adhesion

Aryl Hydrocarbon Receptor Activation in Hematopoietic Stem/Progenitor Cells Alters Cell Function and Pathway-Specific Gene Modulation Reflecting Changes in Cellular Trafficking and Migration

Differential Gene Expression as a Potential Classifier of 2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole-Sensitive and -Insensitive Cell Lines

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