Implication of the adapter ZIP/p62 in the regulation of PPARalpha transcriptional activity by p38-MAPK

Le récepteur activé par les proliférateurs de péroxysomes alpha (PPARa) appartient à la famille des récepteurs nucléaires et joue un rôle majeur dans la régulation du métabolisme des lipides, de l'homéostasie glucidique et des processus inflammatoires. En plus de son activation par un ligand, PPARa est également contrôlé par des processus post-traductionnels comme la phosphorylation. Dans le foie, PPARa est phosphorylé par des kinases comme les MAPKs, la PKA et la PKC. Le but de ce travail était d'étudier l'effet de la p38-MAPK sur l'activité transcriptionnelle de PPARa. Nous avons tout d'abord montré que, dans des cellules COS-7, un activateur de la p38-MAPK, l'anisomycine, phosphorylait PPARa de manière dose dépendante et inhibait de 50% son activité transcriptionnelle. Deuxièmement, dans des hépatomes, la phosphorylation de la p38-MAPK induite par l'anisomycine entraîne une diminution de l'expression endogène de la L-CPT I (liver-carnitine palmitoyltransferase), un gène cible de PPARa. Troisièmement, nous avons démontré que l'interaction PPARa/p38-MAPK nécessite un adaptateur, la protéine ZIP (zêta PKC-interacting protein). En effet, des expériences de co-immunoprécipitation nous ont permis de mettre en évidence une interaction trimèrique entre PPARa, la p38-MAPK et ZIP. Enfin, en diminuant l'expression de ZIP à l'aide d'un siRNA, nous avons observé une réduction de l'effet inhibiteur de l'anisomycine sur l'expression du gène codant la L-CPT I. En conclusion, nous avons montré que l'activation de la p38-MAPK induisait une phosphorylation de PPARa et une inhibition de son activité transcriptionnelle secondairement à la formation d'un trimère PPARa/ZIP/p38-MAPK.PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Relationship of different ovarian stimulation response with vascular endothelial growth factor and degree of granulosa cell apoptosis.

The aim of this study was to evaluate the concentration of vascular endothelial growth factor (VEGF) in follicular fluid and in granulosa cell cultures in relation to the degree of apoptosis in granulosa cells from patients with different types of ovarian response to controlled ovarian hyperstimulation. We studied 30 women who underwent controlled ovarian hyperstimulation and oocyte retrieval. Group A comprised patients with 1-4 follicles (n = 10), group B patients with 5-14 follicles (n = 10) and group C patients with >15 follicles (n = 10).Fil: Quintana, R. Instituto de Ginecología y Fertilidad; ArgentinaFil: Kopcow, L.. Instituto de Ginecología y Fertilidad; ArgentinaFil: Marconi, G.. Instituto de Ginecología y Fertilidad; ArgentinaFil: Sueldo, C.. Instituto de Ginecología y Fertilidad; ArgentinaFil: Diradourian, M.. Instituto de Ginecología y Fertilidad; ArgentinaFil: Barañao, Rosa Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Functions of the peroxisome proliferator-activated receptor (PPAR) alpha and beta in skin homeostasis, epithelial repair, and morphogenesis.

The three peroxisome proliferator-activated receptors (PPAR alpha, PPAR beta, and PPAR gamma) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. They are regarded as being sensors of physiological levels of fatty acids and fatty acid derivatives. In the adult mouse skin, they are found in hair follicle keratinocytes but not in interfollicular epidermis keratinocytes. Skin injury stimulates the expression of PPAR alpha and PPAR beta at the site of the wound. Here, we review the spatiotemporal program that triggers PPAR beta expression immediately after an injury, and then gradually represses it during epithelial repair. The opposing effects of the tumor necrosis factor-alpha and transforming growth factor-beta-1 signalling pathways on the activity of the PPAR beta promoter are the key elements of this regulation. We then compare the involvement of PPAR beta in the skin in response to an injury and during hair morphogenesis, and underscore the similarity of its action on cell survival in both situations

SUMOylation of Human Peroxisome Proliferator-activated Receptor α Inhibits Its Trans-activity through the Recruitment of the Nuclear Corepressor NCoR*

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is a key regulator of genes implicated in lipid homeostasis and inflammation. PPARα trans-activity is enhanced by recruitment of coactivators such as SRC1 and CBP/p300 and is inhibited by binding of corepressors such as NCoR and SMRT. In addition to ligand binding, PPARα activity is regulated by post-translational modifications such as phosphorylation and ubiquitination. In this report, we demonstrate that hPPARα is SUMOylated by SUMO-1 on lysine 185 in the hinge region. The E2-conjugating enzyme Ubc9 and the SUMO E3- ligase PIASy are implicated in this process. In addition, ligand treatment decreases the SUMOylation rate of hPPARα. Finally, our results demonstrate that SUMO-1 modification of hPPARα down-regulates its trans-activity through the specific recruitment of corepressor NCoR but not SMRT leading to the differential expression of a subset of PPARα target genes. In conclusion, hPPARα SUMOylation on lysine 185 down-regulates its trans-activity through the selective recruitment of NCoR