The RIP140 Gene Is a Transcriptional Target of E2F1

RIP140 is a transcriptional coregulator involved in energy homeostasis and ovulation which is controlled at the transcriptional level by several nuclear receptors. We demonstrate here that RIP140 is a novel target gene of the E2F1 transcription factor. Bioinformatics analysis, gel shift assay, and chromatin immunoprecipitation demonstrate that the RIP140 promoter contains bona fide E2F response elements. In transiently transfected MCF-7 breast cancer cells, the RIP140 promoter is transactivated by overexpression of E2F1/DP1. Interestingly, RIP140 mRNA is finely regulated during cell cycle progression (5-fold increase at the G1/S and G2/M transitions). The positive regulation by E2F1 requires sequences located in the proximal region of the promoter (−73/+167), involves Sp1 transcription factors, and undergoes a negative feedback control by RIP140. Finally, we show that E2F1 participates in the induction of RIP140 expression during adipocyte differentiation. Altogether, this work identifies the RIP140 gene as a new transcriptional target of E2F1 which may explain some of the effect of E2F1 in both cancer and metabolic diseases

Retinoic Acid Mediates Long-Paced Oscillations in Retinoid Receptor Activity: Evidence for a Potential Role for RIP140

Mechanisms 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.Here 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.We 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

Tissue-specific expression of receptor-interacting protein in aging mouse

Receptor-interacting protein (RIP) is a well-characterized coregulator for nuclear receptors. Here, we report the expression of RIP as two isoforms with molecular weights of 140 kDa and 137 kDa in liver and kidney, but only as one isoform of 140 kDa in lung, adipose tissue, prostate and testis of mice. The levels of both the isoforms decreased in liver and kidney of old mice compared with adult mice. The expression of RIP140 in kidney was relatively lower in old males than females. In contrast, adipose tissue showed remarkably higher levels of RIP140 in old than adult mice of both sexes. Thus, the expression of RIP varied with the type of tissue, sex and age of mice, suggesting differences in its function as a coregulator

Regulation of hormone signaling by nuclear receptor interacting proteins.

The original publication is available at springerlink.comInternational audienceNuclear receptors are ligand-activated transcription factors which regulate the expression of genes critical for the growth of hormone-dependent cancers. Their expression and activity are controlled by various cofactors which are important players in hormone-dependent carcinogenesis. RIP140 is a negative transcriptional regulator which is recruited by agonist-liganded receptors. Its strong repressive activity involves four silencing domains which interact with histone deacetylases (HDACs), carboxyl-terminal binding proteins (CtBPs) and additional partners. RIP140 positively regulates transactivation when nuclear receptors are recruited to target promoters through interaction with the Sp1 transcription factor. In human breast cancer cells, RIP140 expression is upregulated at the transcriptional level by various ligands of nuclear receptors revealing the existence of regulatory loops. The Mdm2 oncogenic ubiquitin-ligase is another protein which directly interacts with nuclear receptors. It is involved in a ternary complex with ERΑ and p53 and regulates ERΑ turn-over. In MCF-7 human breast cancer cells, various p53-inducing agents (such as UV irradiation) abolished E2-dependent turn-over of ERΑ without affecting its transactivation potential. Altogether, our results show that RIP140 and Mdm2 are two important regulators of ERΑ expression and activity and could therefore play major roles in hormone-dependent breast carcinogenesis

Complex regulation of LCoR signaling in breast cancer cells

International audienceLigand-dependent corepressor (LCoR) is a transcriptional repressor of ligand-activated estrogen receptors (ERs) and other transcription factors that acts both by recruiting histone deacetylases and C-terminal binding proteins. Here, we first studied LCOR gene expression in breast cancer cell lines and tissues. We detected two mRNAs variants, LCoR and LCoR2 (which encodes a truncated LCoR protein). Their expression was highly correlated and localized in discrete nuclear foci. LCoR and LCoR2 strongly repressed transcription, inhibited estrogen-induced target gene expression and decreased breast cancer cell proliferation. By mutagenesis analysis, we showed that the helix-turn-helix domain of LCoR is required for these effects. Using in vitro interaction, coimmunoprecipitation, proximity ligation assay and confocal microscopy experiments, we found that receptor-interacting protein of 140 kDa (RIP140) is a LCoR and LCoR2 partner and that this interaction requires the HTH domain of LCoR and RIP140 N- and C-terminal regions. By increasing or silencing LCoR and RIP140 expression in human breast cancer cells, we then showed that RIP140 is necessary for LCoR inhibition of gene expression and cell proliferation. Moreover, LCoR and RIP140 mRNA levels were strongly correlated in breast cancer cell lines and biopsies. In addition, RIP140 positively regulated LCoR expression in human breast cancer cells and in transgenic mouse models. Finally, their expression correlated with overall survival of patients with breast cancer. Taken together, our results provide new insights into the mechanism of action of LCoR and RIP140 and highlight their strong interplay for the control of gene expression and cell proliferation in breast cancer cells