Received for publication January 29, 2008.
Revised March 20, 2008.
Accepted for publication March 21, 2008.

The Anti-Apoptotic Factor GADD45B Regulates the Nuclear Receptor CAR-Mediated Transcription

Abstract

The nuclear receptor CAR up-regulated expression of the apoptotic GADD45B gene in HepG2 cells. Over expression of GADD45B augmented CAR-mediated induction of the human CYP2B gene by the CAR activator TCPOBOP and co-activated CAR-dependent transcription of the NR1-Luc reporter gene. siRNA knock down of GADD45B resulted in repression of both the induction and the co-activation. Induction of the mouse Cyp2b10 gene by TCPOBOP was profoundly attenuated in the primary hepatocytes prepared from GADD45B-KO mice compared with those from wild type mice. Since CAR is a key transcription factor that activates the genes that encode for xenobiotic metabolizing enzymes and transporters, GADD45B, acting as a CAR co-activator and co-regulating CAR-target genes, may be involved in hepatic drug metabolism and excretion of xenobiotics.

Key words: CAR, cell death, CYP gene regulation, CYP induction, CYP2B, hepatocytes, nuclear receptors, transcriptional regulation