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Role of the Aryl Hydrocarbon Receptor in the Regulation of Cell Cycle Progression in the Absence of Xenobiotic Ligands

Chang, Xiaoqing
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1179423103

Abstract Details

2007, PhD, University of Cincinnati, Medicine : Toxicology (Environmental Health).
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the biologic and toxic effects of its xenobiotic ligands. Besides its role in the regulation of xenobiotic metabolism, increasing evidence indicates that the AHR also plays an important role in cell cycle regulation, but the underlying mechanism is still unclear. In the present study, we further investigated this role using our developed fibroblast cell lines that stably express AHR variants in Ahr-null mouse embryo fibroblasts (MEFs) under the regulation of the tetracycline receptor/repressor system. Three AHR variants were expressed in this system including a high ligand binding affinity AHR, a low ligand binding affinity AHR or a constitutively active truncated mutant of AHR. Cell proliferation study with these AHR variants expressing cell lines indicated that the rate of cell proliferation was significantly faster in AHR-positive than in AHR-negative cells, due to a shortening of the G1 and S phases of the cell cycle. Exposure to the prototypical AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, or deletion of the ligand-binding domain of AHR had no effect on cell growth rates, suggesting that the presence of AHR, but not its activation by ligand, was responsible for the faster proliferation rates. Comparison of global gene expression analyses with cells synchronized in G1 and S showed that growth-promoting genes, such as cyclins and cyclin dependent kinases, were significantly down-regulated in Ahr-/- cells, whereas growth-arresting genes, such as transforming growth factor-beta1 (TGF-b1), extracellular matrix-related genes and cyclin-dependent kinase inhibitors were up-regulated. Ahr-/- fibroblasts secreted significantly more TGF-b1 into the culture medium than Ahr+/+ fibroblasts and showed increased levels of activated SMAD4 as well. The increases in TGF-b1 mRNA and protein levels were due to mRNA stabilization in Ahr-/- cells resulting from decreased activity of tristetraproline (TTP), the mRNA-binding protein responsible for mRNA destabilization through AU-rich motifs. These results show that the Ah receptor modulates cellular functions, such as extracellular matrix formation and cell cycle control, through the regulation of TGF-b1 expression. This intrinsic AHR function is carried out in the absence of xenobiotic ligands.
Dr. Alvaro Puga (Advisor)
165 p.

Recommended Citations

Citations

  • Chang, X. (2007). Role of the Aryl Hydrocarbon Receptor in the Regulation of Cell Cycle Progression in the Absence of Xenobiotic Ligands [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1179423103

    APA Style (7th edition)

  • Chang, Xiaoqing. Role of the Aryl Hydrocarbon Receptor in the Regulation of Cell Cycle Progression in the Absence of Xenobiotic Ligands. 2007. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1179423103.

    MLA Style (8th edition)

  • Chang, Xiaoqing. "Role of the Aryl Hydrocarbon Receptor in the Regulation of Cell Cycle Progression in the Absence of Xenobiotic Ligands." Doctoral dissertation, University of Cincinnati, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1179423103

    Chicago Manual of Style (17th edition)

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© 2007, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.