Abstract
BackgroundMechanisms that underlie oscillatory transcriptional activity of nuclear receptors (NRs) are incompletely understood. Evidence exists for rapid, cyclic recruitment of coregulatory complexes upon activation of nuclear receptors. RIP140 is a NR coregulator that represses the transactivation of agonist-bound nuclear receptors. Previously, we showed that RIP140 is inducible by all-trans retinoic acid (RA) and mediates limiting, negative-feedback regulation of retinoid signaling.Methodology and FindingsHere we report that in the continued presence of RA, long-paced oscillations of retinoic acid receptor (RAR) activity occur with a period ranging from 24 to 35 hours. Endogenous expression of RIP140 and other RA-target genes also oscillate in the presence of RA. Cyclic retinoid receptor transactivation is ablated by constitutive overexpression of RIP140. Further, depletion of RIP140 disrupts cyclic expression of the RA target gene HOXA5. Evidence is provided that RIP140 may limit RAR signaling in a selective, non-redundant manner in contrast to the classic NR coregulators NCoR1 and SRC1 that are not RA-inducible, do not cycle, and may be partially redundant in limiting RAR activity. Finally, evidence is provided that RIP140 can repress and be induced by other nuclear receptors in a manner that suggests potential participation in other NR oscillations.Conclusions and SignificanceWe provide evidence for novel, long-paced oscillatory retinoid receptor activity and hypothesize that this may be paced in part, by RIP140. Oscillatory NR activity may be involved in mediating hormone actions of physiological and pathological importance.
Highlights
The retinoids are derivatives of vitamin A that influence development, differentiation and homeostasis and are pharmacologically valuable in the prevention and treatment of select neoplasms [1,2,3]
We provide evidence for novel, long-paced oscillatory retinoid receptor activity and hypothesize that this may be paced in part, by RIP140
NT2/D1 cells were transiently transfected with a retinoic acid (RA)-responsive luciferase reporter (RARE-tk-Luc), and RA-mediated retinoic acid response elements (RAREs) transactivation was monitored in real time with a LumiCycle instrument
Summary
The retinoids are derivatives of vitamin A that influence development, differentiation and homeostasis and are pharmacologically valuable in the prevention and treatment of select neoplasms [1,2,3]. Positive and negative regulation of gene expression by NRs is contingent upon coordinated interaction with coregulatory molecules (coactivators and corepressors), which nucleate precisely organized chromatin remodeling complexes [5]. In the absence of ligand, interaction of the ligand-binding domain with corepressors such as NCoR1 or NCoR2/SMRT mediates transcriptional repression via recruitment of complexes with enzymatic histone modifying activity [5]. Upon ligand binding, this complex dissociates and the binding of coactivators such as SRC1/NCoA1, SRC2/TIF2/NCoA2 or SRC3/AIB1/NCoA3 enable a transcriptionally permissive chromatin configuration through histone acetylation and other covalent modifications [5]. We showed that RIP140 is inducible by all-trans retinoic acid (RA) and mediates limiting, negative-feedback regulation of retinoid signaling
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
