Expression and role of RIP140/NRIP1 in chronic lymphocytic leukemia

International audienc

The nuclear receptor transcriptional coregulator RIP140

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

Signalisation oestrogènique et cancer du sein (mécanisme d'action et rôle du cofacteur transcriptionnel RIP140)

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Rôle et mécanisme d'action du cofacteur transcriptionnel RIP140 dans la signalisation oestrogénique

La protéine RIP140 est un cofacteur atypique , qui bien que recruté en présence de ligans, réprime l'activité transcriptionnelle de nombreux récepteurs nucléaires. Notre objectif a été de préciser le rôle et les mécanismes d'action de RIP140 dans la signalisation oestogénique. Nous avons montré que RIP140 réprime l'activité des récepteurs des oestogènes et des récepteurs apparentés ERRs lorsqu'ils sont recrutés au niveau de l'ADN. Cette activité répréssive implique les histones désacétylases ainsi que les C-terminal Binding Proteins. Nous avons également identifié deux domaines C-terminaux de RIP140, fortement répresseurs, recrutant problablement d'autres partenaires. Enfin nous avons montré que les ERRs activent la transcription de gènes via les protéines Sp1 (gène p21) et que RIP140 exerce un effet positif sur cette transactivation, impliquant les histones désacétylases. RIP140 apparait donc comme un cofacteur complexe, dont l'effet repose sur de multiples domaines et partenaires.MONTPELLIER-BU Pharmacie (341722105) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Response to ‘Pharmacy‐based interdisciplinary intervention for patients with chronic heart failure: results of the PHARM‐CHF randomized controlled trial’

International audienc

: Vitamine B6 et cancer

International audienceVitamin B6 is well-known for its role as a cofactor in many enzymatic reactions and recently, several epidemiological studies have highlighted the importance of this vitamin as a protective agent against various cancers: elevated vitamin B6 plasma levels were associated with a lower risk of colorectal cancer development, for example. In vivo studies have shown that vitamin B6 decreased cell proliferation and enhanced the immune response. At the cellular level, antioxidant, pro-apoptotic and anti-angiogenic effects have been identified. At the molecular level, vitamin B6 is able to inhibit the transactivation potential of various nuclear receptors. Interestingly, a recent paper has described the conjugation of vitamin B6 to RIP140 (receptor interacting protein of 140 kDa), a protein that acts as a transcriptional corepressor of nuclear receptors. This post-translational modification increases the transcriptional repression of RIP140 and regulates its subcellular localization and its ability to interact with different protein partners. Finally, vitamin B6 is involved in the methyl donor cycle ant thus, some of the antitumor properties of vitamin B6 may involve an indirect effect on the level of DNA or histone methylation. All of these mechanistic and clinical data justify further studies to decipher the mechanism of action of vitamin B6 and its clinical interest in combination with molecules typically used in chemotherapy or hormonal therapy

Rôle de RIP140 dans la signalisation hormonale

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

Patients with diabetes are at high risk of serious medication errors at hospital: Interest of clinical pharmacist intervention to improve healthcare

International audienceBACKGROUND:Medication errors (ME) are major public health issues in hospitals because of their consequences on patients' morbi-mortality. This study aims to evaluate the prevalence of ME at admission and discharge of hospitalization in diabetic and non-diabetic patients, and determine their potential clinical impact.METHOD:This prospective observational study was conducted at the Endocrinology-Diabetology-Nutrition Department. All adult patients admitted were eligible. A total of 904 patients were included, of which 671 (74.2%) with diabetes mellitus. Clinical pharmacists conducted medication reconciliation: they collected the Best Possible Medication History and then compared it with admission and discharge prescriptions to identify medication discrepancies. ME were defined as unintended medication discrepancies if corrected by the physician.RESULTS:Clinical pharmacists allowed correcting ME in 176/904 (19.5%) patients at admission and in 86/865 (9.9%) patients at discharge. More than half of ME were omissions. Diabetic patients were more affected by ME than non-diabetic patients, both at admission (22.1% vs 12.0%, p<0.001) and at discharge (11.4% vs 5.7%, p=0.01). The diabetic group also had more potentially severe and very severe ME. Diabetic patients had on average twice more medications than non-diabetic patients (8.7±4.5 vs 4.4±3.4, p<0.001). The polypharmacy associated with diabetes, but not diabetes mellitus itself, was identified as a risk factor of ME.CONCLUSIONS:The intervention of clinical pharmacists allowed correcting 378 ME in 25.8% of the cohort before they caused harm. Clinicians, pharmacists and other health care providers should therefore work together to improve patients' safety, in particular in high-risk patients such as diabetic patients

Dialogue between estrogen receptor and E2F signaling pathways: The transcriptional coregulator RIP140 at the crossroads

International audienceEstrogen receptors and E2F transcription factors are the key players of two nuclear signaling pathways which exert a major role in oncogenesis, particularly in the mammary gland. Different levels of dialogue between these two pathways have been deciphered and deregulation of the E2F pathway has been shown to impact the response of breast cancer cells to endocrine therapies. The present review focuses on the transcriptional coregulator RIP140/NRIP1 which is involved in several regulatory feed-back loops and inhibitory cross-talks between different nuclear signaling pathways. RIP140 regulates the transactivation potential of estrogen receptors and E2Fs and is also a direct transcriptional target of these transcription factors. Published data highlight the complex regulation of RIP140 expression at the transcriptional level and its potential role in transcription cross-talks. Indeed, a subtle regulation of RIP140 expression levels has important consequences on other transcription networks targeted by this coregulator. Another level of regulation implies titration mechanisms by which activation of a pathway leads to sequestration of the RIP140 protein and thus impinges other gene regulatory circuitries. Altogether, RIP140 occupies a place of choice in the dialogue between nuclear receptors and E2Fs, which could be highly relevant in various human pathologies such as cancer or metabolic diseases

The emerging role of the transcriptional coregulator RIP140 in solid tumors

International audienceRIP140 is a transcriptional coregulator (also known as NRIP1) which plays very important physiological roles by finely tuning the activity of a large number of transcription factors. Noticeably, the RIP140 gene has been shown to be involved in the regulation of energy expenditure, in mammary gland development and intestinal homeostasis as well as in behavior and cognition. RIP140 is also involved in the regulation of various oncogenic signaling pathways and participates in the development and progression of solid tumors. This short review aims to summarize the role of this transcription factor on nuclear estrogen receptors, E2F and Wnt signaling pathways based on recent observations focusing on breast, ovary, liver and colon tumors