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Molecular and Cellular Biology, September 2007, p. 6127-6139, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00323-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Ligand-Independent Regulation of Transforming Growth Factor ß1 Expression and Cell Cycle Progression by the Aryl Hydrocarbon Receptor{triangledown} ,{dagger}

Xiaoqing Chang,1 Yunxia Fan,1 Saikumar Karyala,1 Sandy Schwemberger,2 Craig R. Tomlinson,1,{ddagger} Maureen A. Sartor,1 and Alvaro Puga1*

Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, Ohio 45267-0056,1 Shriners Hospital for Children, Cincinnati, Ohio 452292

Received 22 February 2007/ Returned for modification 21 March 2001/ Accepted 19 June 2007

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic effects of its xenobiotic ligands and acts as an environmental checkpoint during the cell cycle. We expressed stably integrated, Tet-Off-regulated AHR variants in fibroblasts from AHR-null mice to further investigate the AHR role in cell cycle regulation. Ahr+/+ fibroblasts proliferated significantly faster than Ahr–/– fibroblasts did, and exposure to a prototypical AHR ligand or deletion of the ligand-binding domain did not change their proliferation rates, indicating that the AHR function in cell cycle was ligand independent. Growth-promoting genes, such as cyclin and cyclin-dependent kinase genes, were significantly down-regulated in Ahr–/– cells, whereas growth-arresting genes, such as the transforming growth factor ß1 (TGF-ß1) gene, extracellular matrix (ECM)-related genes, and cyclin-dependent kinase inhibitor genes, were up-regulated. Ahr–/– fibroblasts secreted significantly more TGF-ß1 into the culture medium than Ahr+/+ fibroblasts did, and Ahr–/– showed increased levels of activated Smad4 and TGF-ß1 mRNA. Inhibition of TGF-ß1 signaling by overexpression of Smad7 reversed the proliferative and gene expression phenotype of Ahr–/– fibroblasts. Changes in TGF-ß1 mRNA accumulation were due to stabilization resulting from decreased activity of TTP, the tristetraprolin RNA-binding protein responsible for mRNA destabilization through AU-rich motifs. These results show that the Ah receptor possesses interconnected intrinsic cellular functions, such as ECM formation, cell cycle control, and TGF-ß1 regulation, that are independent of activation by either exogenous or endogenous ligands and that may play a crucial role during tumorigenesis.

* Corresponding author. Mailing address: Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267-00567. Phone: (513) 558-0916. Fax: (513) 558-0925. E-mail: Alvaro.Puga{at}UC.edu

{triangledown} Published ahead of print on 2 July 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Department of Medicine, Dartmouth University Hitchcock Medical Center, Lebanon, NH 03756.

Molecular and Cellular Biology, September 2007, p. 6127-6139, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00323-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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