Interplay of Pregnane X receptor with Other Nuclear Receptors on Gene Regulation

2008 ◽  
Vol 23 (1) ◽  
pp. 14-21 ◽  
Author(s):  
Yun-Ping Lim ◽  
Jin-ding Huang
Keyword(s):  
Gene Regulation ◽  
Nuclear Receptors ◽  
Pregnane X Receptor

scholarly journals Nuclear receptor phosphorylation in xenobiotic signal transduction

2020 ◽  
Vol 295 (45) ◽  
pp. 15210-15225 ◽  
Author(s):  
Masahiko Negishi ◽  
Kaoru Kobayashi ◽  
Tsutomu Sakuma ◽  
Tatsuya Sueyoshi
Keyword(s):  
Dna Binding ◽  
Cell Signaling ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Pregnane X Receptor ◽  
Receptor Activation ◽  
Binding Domain ◽  
Activation Mechanism ◽  
Dna Binding Domain ◽  
Phosphorylation Motif

Nuclear pregnane X receptor (PXR, NR1I2) and constitutive active/androstane receptor (CAR, NR1I3) are nuclear receptors characterized in 1998 by their capability to respond to xenobiotics and activate cytochrome P450 (CYP) genes. An anti-epileptic drug, phenobarbital (PB), activates CAR and its target CYP2B genes, whereas PXR is activated by drugs such as rifampicin and statins for the CYP3A genes. Inevitably, both nuclear receptors have been investigated as ligand-activated nuclear receptors by identifying and characterizing xenobiotics and therapeutics that directly bind CAR and/or PXR to activate them. However, PB, which does not bind CAR directly, presented an alternative research avenue for an indirect ligand-mediated nuclear receptor activation mechanism: phosphorylation-mediated signal regulation. This review summarizes phosphorylation-based mechanisms utilized by xenobiotics to elicit cell signaling. First, the review presents how PB activates CAR (and other nuclear receptors) through a conserved phosphorylation motif located between two zinc fingers within its DNA-binding domain. PB-regulated phosphorylation at this motif enables nuclear receptors to form communication networks, integrating their functions. Next, the review discusses xenobiotic-induced PXR activation in the absence of the conserved DNA-binding domain phosphorylation motif. In this case, phosphorylation occurs at a motif located within the ligand-binding domain to transduce cell signaling that regulates hepatic energy metabolism. Finally, the review delves into the implications of xenobiotic-induced signaling through phosphorylation in disease development and progression.

Regulation of CYP3A4 by pregnane X receptor: The role of nuclear receptors competing for response element binding

2010 ◽  
Vol 393 (4) ◽  
pp. 688-693 ◽  
Author(s):  
Monica A. Istrate ◽  
Andreas K. Nussler ◽  
Michel Eichelbaum ◽  
Oliver Burk
Keyword(s):  
Nuclear Receptors ◽  
Pregnane X Receptor ◽  
Response Element
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