title: Ah receptor-mediated suppression of liver regeneration through NC-XRE-driven p21Cip1 expression.
abstract: Previous studies in hepatocyte-derived cell lines and the whole liver established that the aryl hydrocarbon receptor (AhR) can disrupt G1-phase cell cycle progression following exposure to persistent AhR agonists, such as TCDD (dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin). Growth arrest was attributed to inhibition of G1-phase cyclin-dependent kinase 2 (CDK2) activity. The present study examined the effect of TCDD exposure on liver regeneration following 70% partial hepatectomy in mice lacking the Cip/Kip inhibitors p21(Cip1) or p27(Kip1) responsible for regulating CDK2 activity. Assessment of the regenerative process in wild-type, p21(Cip1) knockout, and p27(Kip1) knockout mice confirmed that TCDD-induced inhibition of liver regeneration is entirely dependent on p21(Cip1) expression. Compared with wild-type mice, the absence of p21(Cip1) expression completely abrogated the TCDD inhibition, and accelerated hepatocyte progression through G1 phase during the regenerative process. Analysis of the transcriptional response determined that increased p21(Cip1) expression during liver regeneration involved an AhR-dependent mechanism. Chromatin immunoprecipitation studies revealed that p21(Cip1) induction required AhR binding to the newly characterized nonconsensus xenobiotic response element, in conjunction with the tumor suppressor protein Kruppel-like factor 6 functioning as an AhR binding partner. The evidence also suggests that AhR functionality following partial hepatectomy is dependent on a p21(Cip1)-regulated signaling process, intimately linking AhR biology to the G1-phase cell cycle program.
authors.affiliation: Department of Pharmacology and Toxicology (D.P.J., A.D.J., C.J.E.) and Department of Pediatrics (H.L.), University of Texas Medical Branch, Galveston, Texas; and Department of Biological Sciences, Boise State University, Boise, Idaho (K.A.M.).
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Jackson
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Mitchell
authors.forename: Aditya D
authors.initials: AD
authors.lastname: Joshi
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Elferink
mesh_terms: D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D006498:Hepatectomy; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008115:Liver Regeneration; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism*; D020218:Response Elements
chemical_list: C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D000072317:Polychlorinated Dibenzodioxins; D011518:Proto-Oncogene Proteins; D018336:Receptors, Aryl Hydrocarbon; D050760:Cyclin-Dependent Kinase Inhibitor p27