Rôle de RIP140 dans la signalisation hormonale

Abstract

Les récepteurs nucléaires forment une superfamille de facteurs de transcription, qui contrôlent de nombreux aspects du métabolisme cellulaire et dont l’activité est réglée par un grand nombre de ligands et de cofacteurs transcriptionnels. RIP140 (receptor interacting protein of 140 kDa), un des premiers corégulateurs identifiés, est une protéine atypique qui, si elle interagit avec les récepteurs nucléaires en présence de ligands agonistes, exerce un contrôle négatif sur leur activité transcriptionnelle. Les mécanismes responsables de cette transrépression sont complexes et impliquent plusieurs domaines, recrutant différents partenaires tels que les protéines HDAC (histone désacétylase) et CtBP (C-terminal binding protein). Le contrôle de l’expression du gène RIP140 dans les cellules de cancers hormonodépendants semble intéressant, car il implique des possibilités de boucles de régulations multiples. Enfin, l’étude du rôle biologique de RIP140 suggère qu’il est impliqué dans le contrôle hormonal de processus fondamentaux tels que l’ovulation et la thermogenèse.

Nuclear hormone receptors belong to a superfamily of ligand-activated transcription factors which regulate fundamental physiological processes. Their activity is controlled by a large number of coregulatory proteins which are, in most cases, recruited by nuclear receptors in the presence of ligand. RIP140 (receptor interacting protein of 140 kDa) was one of the first transcription cofactors to be identified almost ten years ago. This molecule is an atypical cofactor which interacts with agonist-liganded nuclear receptors but negatively regulates their transactivation potential. RIP140 exhibits nine leucine-rich motifs (LxxLL) which mediate the specific docking on the nuclear receptor ligand-binding domain. Transcription repression exerted by this cofactor implicates different mechanisms. Not only it involves a competition with coactivators such as those belonging to the p160 family, but also relies on active intrinsic repression through at least four different domains which allow recruitement of downstream repressors such as histone deacetylases (HDACs) or C-terminal binding proteins (CtBPs). The biological role of RIP140 has been investigated by disrupting the gene in mice. The lack of RIP140 expression in ovaries prevents follicle rupture and ovulation, rising to female infertility. In addition, this cofactor is also required for the control of fat storage and utilization through the regulation of genes involved in thermogenesis. Finally, RIP140 could play a role in the hormonal control of cancer cell proliferation by negatively regulating the activity of estrogen and retinoic acid receptors which are key actors in cancer growth. Interestingly, both estrogens and retinoic acid regulate RIP140 gene expression, revealing an increased level of complexity. In conclusion, RIP140 is an atypical transcription inhibitor which, by repressing nuclear hormone receptor activity, plays fundamental physiopathological roles.