Vitamin A (the retinoids) exerts a wide variety of effects on biological processes, and are commonly used for preventive and therapeutic purposes. Their action is mediated primarily by two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid receptors (RXRs), which regulate gene expression by recruiting coactivators in the presence of retinoic acid (RA) and corepressors in its absence. Nuclear Receptor Interacting Protein 1 (NRIP1), previously named RIP140, is a novel corepressor that represses gene expression in the presence of hormones. It is hypothesized that NRIP1 serves as a ligand-dependent, negative coregulator for hormone-elicited gene regulatory circuits to silence specific gene expression in the presence of hormones.
Three aims are proposed to test this hypothesis by using the RAR/RXR system.
The first aim i s to vigorously examine the molecular basis of NRIP1 interaction with holo-RAR/RXR, which involves a novel C-terminal motif of NRIP1 (PRLTKTNPILYYMLQK) that diverts from a typical coactivator motif, LXXLL, or a corepressor motif, CoRNR box.
The second aim i s to compare NRIP 1 complex to a typical ligand-dependent coactivator complex, SRC-1, with regards to the efficiency of their interaction with receptors and their specific associate proteins.
The third aim i s to address the physiological relevance of RA- dependent corepressor activity of NRIP1 by a) testing the effects of NRIP1 on Oct-3/4 gene that is directly suppressed by RA through RAR/RXR binding to an RA response element (RARE) RAREoct, and b) comparing the effects of coactivator SRC-1 on RARbeta2 gene that is directly induced by RA through a typical DR5 type RARE. Studies proposed in the three aims will advance our understanding of the diversity of molecular mechanisms mediating the effects of vitamin A hormones. Additionally, we will test whether the current working model of hormone nuclear receptor- coregulator can be modified to accomodate complicated actions of hormones in different biological systems. Finally, it is our ultimate goal to determine if the unique property of NRIP1 bears a physiological relevance in terms of the specificity of vitamin A action on a particular gene promoter.
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