Negative feedback at the level of nuclear receptor coregulation. Self-limitation of retinoid signaling by RIP140.

Nuclear receptor-mediated gene expression is proposed to be regulated by the ordered recruitment of large protein complexes in which activity depends on mutual interactions and posttranslational modifications. In contrast, relatively little attention has been given to mechanisms regulating the expression of the coregulator proteins themselves. Previously we have shown that the ligand-dependent corepressor, RIP140, is a direct transcriptional target of all-trans retinoic acid (RA). Here we demonstrate that RA induction of RIP140 constitutes a rate-limiting step in the regulation of retinoic acid receptor signaling. Silencing of the RA induction of RIP140 dramatically enhances and accelerates retinoid receptor transactivation, endogenous expression of other RA target genes, and RA-induced neuronal differentiation and cell cycle arrest in human embryonal carcinoma cells. The data suggest that RA induction of RIP140 constitutes a functional negative feedback loop that limits activation of retinoid receptors in the continued presence of RA and that acutely regulated expression of coregulators may be a general regulatory mechanism in hormonal signaling.