The nuclear receptor transcriptional coregulator RIP140

Abstract

The nuclear receptor superfamily comprises ligand-regulated transcription factors that control various developmental and physiological pathways. These receptors share a common modular structure and regulate gene expression through the recruitment of a large set of coregulatory proteins. These transcription cofactors regulate, either positively or negatively, chromatin structure and transcription initiation. One of the first proteins to be identified as a hormone-recruited cofactor was RIP140. Despite its recruitment by agonist-liganded receptors, RIP140 exhibits a strong transcriptional repressive activity which involves several inhibitory domains and different effectors. Interestingly, the RIP140 gene, located on chromosome 21 in humans, is finely regulated at the transcriptional level by various nuclear receptors. In addition, the protein undergoes several post-translational modifications which control its repressive activity. Finally, experiments performed in mice devoid of the RIP140 gene indicate that this transcriptional cofactor is essential for female fertility and energy homeostasis. RIP140 therefore appears to be an important modulator of nuclear receptor activity which could play major roles in physiological processes and hormone-dependent diseases.

Figure 1. Schematic representation of RIP140 structure.

The boxes represent the RIP140 molecule showing respectively the different functional domains together with post-translational modifications and single nucleotide polymorphisms. The numbers correspond to the amino acid position on the molecule. A) Repression domains (RD). The four domains (RD1 to 4) map respectively to the regions located between residues 27 and 199 429 and 700, 753 to 804 and 1118 to 1158 (Castet et al. 2004; Christian et al. 2004; Vo et al. 2001; Wei et al. 2000; Wei et al. 2001). B) Interacting motifs. The ten LxxLL NR binding sites (Heery et al. 1997) and the atypical LxxML motif (Chen et al. 2002) are shown together with the two putative nuclear localization signals at position 97 and 856, the 14-3-3 binding motif (RTFSYP) (Zilliacus et al. 2001) and the CtBP binding sites PIDLS and PINLS at position 440 and 565 (Castet et al. 2004; Christian et al. 2004; Vo et al. 2001). C) Post-translational modifications. The figure shows phosphorylation (S104, S358, S380, S488, S519, S531, S543, S672, S1003, T202 and T207) (Huq et al. 2005a; Gupta et al. 2005) and acetylation sites (K111, K118, K287, K211, K446, K482, K529, K607, K932) (Huq and Wei 2005b; Vo et al. 2001). D) Single nucleotide polymorphism (SNPs). The six SNPs causing amino acid sequence changes in the human RIP140 protein correspond to G75G, H221R, Y315F, I441V, R448G, S803L (Caballero et al. 2005).