Identification of Stanniocalcin 2 as a Novel Aryl Hydrocarbon Receptor Target Gene

Abstract

Abstract Proper hepatocyte function is vital for survival; hence unrepaired destruction of the parenchymal tissue leading to liver decompensation is devastating. Therefore, understanding the homeostatic process regulating liver regeneration is clinically important, and evidence that the Aryl hydrocarbon Receptor (AhR) can promote cell survival following intrinsic apoptotic stimuli is integral to the regenerative process. The current study utilizes primary hepatocytes to identify survival mechanisms consistent with normal AhR biology. Taking advantage of the Cre-lox system to manipulate AhR status, we designed a comprehensive microarray analysis to identify immediate and direct changes in the transcriptome concomitant with the loss of the AhR. As a result we identified a unique data set with minimal overlap compared to previous array studies culminating in the identification of Stanniocalcin 2 (Stc2) as a novel receptor target gene previously reported to have a cytoprotective role in endoplasmic reticulum stress. The Stc2 promoter contains multiple putative xenobiotic response elements (XRE) clustered in a 250 bp region that was shown to recruit the AhR by chromatin immunoprecipitation. Interestingly, Stc2 gene expression is refractory to classic exogenous AhR agonists, but responds to cellular stress in an AhR-dependent mechanism consistent with a process promoting cell survival. JPET #201111