QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 20, Issue 6, 1715-1727, March 15, 2009

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E08-05-0451v1 20/6/1715    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carvajal-Gonzalez, J. M. Articles by Fernandez-Salguero, P. M. Search for Related Content PubMed PubMed Citation Articles by Carvajal-Gonzalez, J. M. Articles by Fernandez-Salguero, P. M.

The Dioxin Receptor Regulates the Constitutive Expression of the Vav3 Proto-Oncogene and Modulates Cell Shape and Adhesion

Jose M. Carvajal-Gonzalez^*, Sonia Mulero-Navarro^*, Angel Carlos Roman^*, Vincent Sauzeau, Jaime M. Merino^*, Xose R. Bustelo, and Pedro M. Fernandez-Salguero^*

*Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain; and Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Campus Unamuno, 37007 Salamanca, Spain

Submitted May 2, 2008; Revised December 2, 2008; Accepted January 8, 2009
Monitoring Editor: Josephine C. Adams

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 down-regulation 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.

Address correspondence to: Pedro M. Fernandez-Salguero (pmfersal{at}unex.es)

Abbreviations used: AhR, aryl hydrocarbon (dioxin) receptor; FGM, immortalized mouse fibroblasts; FN, fibronectin; GAP, GTPase-activating protein; GEF, guanosine diphosphate/guanosine triphosphate exchange factor; MEF, mouse embryonic fibroblast; YFP, yellow fluorescent protein.

This article has been cited by other articles:

				A. Ambolet-Camoit, L. C. Bui, S. Pierre, A. Chevallier, A. Marchand, X. Coumoul, M. Garlatti, K. Andreau, R. Barouki, and M. Aggerbeck 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Counteracts the p53 Response to a Genotoxicant by Upregulating Expression of the Metastasis Marker AGR2 in the Hepatocarcinoma Cell Line HepG2 Toxicol. Sci., June 1, 2010; 115(2): 501 - 512. [Abstract] [Full Text] [PDF]

				H. I. Fraser, C. A. Dendrou, B. Healy, D. B. Rainbow, S. Howlett, L. J. Smink, S. Gregory, C. A. Steward, J. A. Todd, L. B. Peterson, et al. Nonobese Diabetic Congenic Strain Analysis of Autoimmune Diabetes Reveals Genetic Complexity of the Idd18 Locus and Identifies Vav3 as a Candidate Gene J. Immunol., May 1, 2010; 184(9): 5075 - 5084. [Abstract] [Full Text] [PDF]

				A. C. Roman, J. M. Carvajal-Gonzalez, E. M. Rico-Leo, and P. M. Fernandez-Salguero Dioxin Receptor Deficiency Impairs Angiogenesis by a Mechanism Involving VEGF-A Depletion in the Endothelium and Transforming Growth Factor-{beta} Overexpression in the Stroma J. Biol. Chem., September 11, 2009; 284(37): 25135 - 25148. [Abstract] [Full Text] [PDF]