A system-level investigation into the cellular toxic response mechanism mediated by AhR signal transduction pathway.
BACKGROUND
Viewing a cellular system as a collection of interacting parts can lead to new insights into the complex cellular behavior. In this study, we have investigated aryl hydrocarbon receptor (AhR) signal transduction pathway from such a system-level perspective. AhR detects various xenobiotics, such as drugs or endocrine disruptors (e.g. dioxin), and mediates transcriptional regulation of target genes such as those in the cytochrome P450 (CYP450) family. On binding with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), however, AhR becomes abnormally activated and conveys toxic effects on cells. Despite many related studies on the TCDD-mediated toxicity, quantitative system-level understanding of how TCDD-mediated toxicity generates various toxic responses is still lacking.


RESULTS
Here, we present a manually curated TCDD-mediated AhR signaling pathway including crosstalks with the hypoxia pathway that copes with oxygen deficiency and the p53 pathway that induces a DNA damage response. Based on the integrated pathway, we have constructed a mathematical model and validated it through quantitative experiments. Using the mathematical model, we have investigated: (i) TCDD dose-dependent effects on AhR target genes; (ii) the crosstalk effect between AhR and hypoxia signals; and (iii) p53 inhibition effect of TCDD-liganded AhR. Our results show that cellular intake of TCDD induces AhR signaling pathway to be abnormally up-regulated and thereby interrupts other signaling pathways. Interruption of hypoxia and p53 pathways, in turn, can incur various hazardous effects on cells. Taken together, our study provides a system-level understanding of how AhR signal mediates various TCDD-induced toxicities under the presence of hypoxia and/or DNA damage in cells.
Gim
Jungsoo
J
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), 335 Gwahangno, Yuseong-gu, Daejeon 305-701, Republic of Korea.
Kim
Ho-Shik
HS
Kim
Junil
J
Choi
Minsoo
M
Kim
Jeong-Rae
JR
Chung
Yeun Jun
YJ
Cho
Kwang-Hyun
KH
D015687:Cell Hypoxia; D003198:Computer Simulation; D004249:DNA Damage; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D008962:Models, Theoretical; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D016159:Tumor Suppressor Protein p53