Nuclear receptor phosphorylation in xenobiotic signal transduction
Autor: | Masahiko Negishi, Tatsuya Sueyoshi, Tsutomu Sakuma, Kaoru Kobayashi |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Zinc finger Regulation of gene expression Cell signaling Pregnane X receptor 030102 biochemistry & molecular biology Chemistry JBC Reviews Receptors Cytoplasmic and Nuclear Cell Biology Biochemistry Cell biology Xenobiotics 03 medical and health sciences 030104 developmental biology Nuclear receptor Cytochrome P-450 Enzyme System Phosphorylation Animals Signal transduction Receptor Molecular Biology Signal Transduction |
Zdroj: | J Biol Chem |
ISSN: | 1083-351X |
Popis: | 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. |
Databáze: | OpenAIRE |
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