These differences in ligand-receptor interaction may contribute to the differential recruitment of coactivators to VDR and selective biological actions (7).Nuclear receptors are ligand-inducible transcription factors that are involved in many biological processes, including cell growth and differentiation, embryonic development, and metabolic homeostasis (8). Recently, nuclear receptors belonging to the NR1H and NR1I subfamilies, including VDR, have been shown to control cholesterol Abbreviations: BSEP, bile salt export pump; CAR, constitutive androstane receptor; ER, estrogen receptor; FXR, farnesoid X receptor; IBABP, ileal bile acid binding protein;
Adalimumab, especially with concomitant use of MTX, provided significant improvement in disease activity, without any unexpected ADRs in Japanese RA patients.
The steroid and xenobiotic receptor (SXR) is an orphan nuclear receptor that plays a key role in the regulation of xenobiotic response by controlling the expression of drug metabolizing and clearance enzymes. We observed that pregnane X receptor (PXR), the mouse ortholog of SXR, was retained in the cytoplasm of hepatic cells of untreated mice, whereas PXR was translocated to the nucleus after administration of a ligand, pregnenolone 16␣-carbonitrile. To understand the molecular mechanisms underlying the xenochemical-dependent nuclear translocation of SXR, we identified the signal sequence of SXR that regulates its nuclear translocation; using an in vitro expression system, we allocated the nuclear localization signal (NLS) to amino acid residues 66 to 92 within the DNA binding domain of SXR. The NLS of SXR is characterized as the bipartite type, and is recognized by the three molecular species of importin ␣: Rch1 (PTAC58), NPI1, and Qip1, in the presence of PTAC97 of importin  to target the nuclear pore. The nuclear translocation of SXR was observed as an essential regulatory event for transcription of its target genes such as CYP3A4. These results strongly suggest that the molecular mechanism of the nuclear import of SXR was different from that of another xenosensor, the constitutively active receptor, whose translocation into the nucleus is mediated by a leucine-rich xenochemical response signal in its ligand binding domain.
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