CAR and PXR are members of the NR1I subfamily within the nuclear receptor superfamily. My laboratory was the first to characterize CAR as a drug-activated nuclear receptor, leading world-wide investigations to characterize CAR and PXR and establish their biological roles. Both CAR and PXR regulate not only hepatic drug metabolism and disposition but also energy metabolism such as gluconeogenesis and lipogenesis and ketogenesis. In addition, they regulate cell growth and death signals as well, which includes JNK1, p38MAPK, AKT and GADD45 signals. Consequently, CAR and PXR have now been implicated in various hepatic toxicities and diseases such as liver tumors. It is now known that these receptors act as transcription factors as well as signal transducers in these regulations. However, their molecular mechanisms are not fully understood now. Our work found that CAR is phosphorylated at threonine 38 within the DBD and is inactivated. This phosphorylation is the underlying principle through which CAR functions diverge. For example, phenobarbital stimulates dephosphorization of threonine 38 by protein phosphatase 2A, by binding EGF receptor and/or insulin receptor and repressing their down-stream ERK1/2 signal for CAR activation. In PXR, phosphorylation of serine 350 within the LBD regulates its functions. These phosphorylation motifs within the DBD or LBD are conserved in the majority of nuclear receptors, suggesting that findings with CAR and PXR can be implicated in the investigations of numerous other nuclear receptors Estrogen receptor (ER) conserves threonine 38 of CAR at serine 216 within its DBD. With a phospho-Ser216peptide antibody, it was found that ER is specifically phosphorylated at serine 216 in immune cells such as neutrophils and macrophages in mice. ER KI (Esr1S216A) mice bearing a non-phosphomimetic alanine mutation were generated to investigate the biological roles of this phosphorylation. ER KI mice are fertile but develop obesity. Analysis of brains and microglia and Kupffer cells (resident macrophages in the brain or liver) showed that this phosphorylation confers anti-inflammatory and anti-apoptotic capabilities to ER Phosphorylated ER can be a novel target to investigate various diseases such as obesity and inflammation-related neurodegenerative diseases and their mechanisms. ER KI mice can be an excellent animal model for these investigations. Retinoid related orphan receptor (ROR) conserves this phosphorylation at serine 100 within the DBD. This serine residue becomes phosphorylated in mouse livers in response to phenobarbital treatment, regulating CAR-targeted genes. These nuclear receptors appears to communicate through the conserved phosphorylation, regulating genes and disease developments in response to environmental chemicals and providing an excellent experimental system to investigate the molecular mechanism of this communication. in response to drug treatments and/or physiological/pathophysiological conditions. There are 40 nuclear receptors which conserve this motif with the DBD, enabling us to extend the same line of communication study far beyond these three nuclear receptors.
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