NuclearReceptors2018 Oral Communications (1) (8 abstracts)
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
The Nuclear Receptor (NR) Super-family is a group of ligand modulated transcription factors with 48 members presently identified in human genome. NRs regulate most of the physiological processes of the body ranging from metabolism to reproduction. Retinoid X Receptor (RXR) is one of the important members of this NR superfamily. It serves as a heterodimeric partner of several other members of this superfamily including two major xenobiotic nuclear receptors i.e. Pregnane and Xenobiotic Receptor (PXR) and Constitutive Androstane Receptor (CAR). The latter two receptors are primarily involved in the regulation of bodys metabolism and clearance of endobiotics and xenobiotics (including clinical drugs). In the present study we have investigated the exact subcellular location resulting due to the interaction of RXR with either PXR or CAR. In order to study this event, we have used various GFP- and RFP-tagged receptors and their mutants of nuclear localization signal (NLS) region. The study showed that the initial interaction of RXR-PXR and RXR-CAR occurs in the cytoplasmic compartment of the cell and the NLS of PXR/CAR/RXR play a key role in the import of the heterodimeric complex from the cytoplasm to the nucleus in a ligand-independent manner. Our observtions exhibit that a functional NLS, along with respective ligand(s), are necessary for modulation of the target gene. It is observed that RXR serves as a major driving force in importing the heterodimeric complex to the nuclear compartment. This conclusion is based on the fact that mutation in the NLS region of RXR severly weakens this import process. On the contrary, mutations in the NLS regions of PXR and CAR have little or no significant effect. This RXR-dependent nuclear import of the RXR-PXR and RXR-CAR heterodimeric complex also modulates the individual transcriptional activity of PXR and CAR. Such an enhancement in the basal transcriptional activity of the receptor can be utilized for evaluating the diverse receptor-drug interactions.