Ah Receptor–Mediated Suppression of Liver Regeneration Through NC-XRE–Driven p21^Cip1 Expression

Authors

Daniel P. Jackson, University of Texas Medical Branch
Hui Li, University of Texas Medical Branch
Kristen A. Mitchell, Boise State UniversityFollow
Aditya D. Joshi, University of Texas Medical Branch
Cornelis J. Elferink, University of Texas Medical Branch

Document Type

Article

Publication Date

4-2014

DOI

http://dx.doi.org/10.1124/mol.113.089730

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^Kip1responsible 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^Cip1expression. 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.

Publication Information

Jackson, Daniel P.; Li, Hui; Mitchell, Kristen A.; Joshi, Aditya D.; and Elferink, Cornelis J.. (2014). "Ah Receptor–Mediated Suppression of Liver Regeneration Through NC-XRE–Driven p21^Cip1 Expression". Molecular Pharmacology, 85(4), 533-541.