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  • PI K Akt signaling pathway

    2021-04-09

    PI3K/Akt signaling pathway is known in modulating cell apoptotic process (Saurus et al., 2015). To study the contribution of PI3K/Akt signaling pathway in ERRγ-mediated anti-apoptotic effect in podocytes, we examined phosphorylation of Akt and expression of PI3K subunits p110α and p85α via qRT-PCR and/or Western blotting following the transfection of ERRγ plasmid. Strikingly, overexpression of ERRγ led to a significant increase of phosphorylated Akt and upregulation of PI3K subunits (p110α and p85α), which suggested a regulation of ERRγ on PI3K/Akt signaling. To test the role of PI3K/Akt signaling in ERRγ-mediated anti-apoptotic effect under PAN treatment, a specific PI3K inhibitor LY294002 was administered to the evofosfamide sale (Gharbi et al., 2007). As expected, LY294002 remarkably blocked ERRγ-mediated phosphorylation of Akt. Meantime, the anti-apoptotic effect of ERRγ in PAN-treated podocytes was entirely abolished by the administration of LY294002. All these data highly suggested that PI3K/Akt signaling pathway mediated ERRγ effect on opposing the podocyte apoptosis caused by PAN (Fig. 10).
    Conflict of interest
    Introduction The nuclear receptor superfamily consists of transcription factors that depend on ligands for their activation and a larger group of transcription factors with unidentified ligands or no ligand requirement (reviewed in Mangelsdorf et al., 1995). This latter group of nuclear orphan receptors (reviewed in Giguere, 1999) has diverse biological roles in tissue development and maintenance of homeostasis. Estrogen-related receptors (ERRs) belong to the NR3B orphan nuclear receptor subgroup, which consists of three members α, β and γ (Committee, 1999). ERRα and ERRβ were cloned based on sequence identity to the estrogen receptor alpha (ERα) DNA binding domain (Giguere et al., 1988) whereas the ERRγ was identified by a yeast two-hybrid screen (Hong et al., 1999). As with other nuclear receptors, ERRs are organized into modular domains with a less characterized N-terminal domain, a highly conserved DNA binding (DBD) domain, and a potential ligand binding (LBD) domain that houses the activation function (AF2) domain. It is controversial whether a ligand is needed for ERR activation function (Kamei et al., 2003, Vanacker et al., 1999, Xie et al., 1999, Zhang and Teng, 2000). Recent crystallography studies suggest that the ERR functions as a constitutive activator and the classical nuclear receptor ligand is not required for its function (Greschik et al., 2002, Kallen et al., 2004). Nonetheless, several potential ligands that either stimulate or repress activity of the ERRs have been reported (Coward et al., 2001, Suetsugi et al., 2003, Tremblay et al., 2001, Willy et al., 2004, Yang and Chen, 1999, Zuercher et al., 2005). ERRα has been found to enhance the ERα-mediated response of the human lactoferrin gene promoter via binding to an ERRE site. This site, TCAAGGTCA, is located 18bp upstream from the well-characterized estrogen response element (ERE) (Yang et al., 1996). In contrast, ERRα and ERα function as a competitive repressor in transactivation activity on the synthetic EREs and natural promoter (Giguere, 2002, Johnston et al., 1997, Xie et al., 1999, Zhang and Teng, 2000, Zhang et al., 2006). The relationship of ERRα and ERα in the estrogen signaling pathway, therefore, is significantly influenced by the enhancer element organization of the target gene and the availability of cofactors in a given cellular environment. Recently, ERRα was reported to be upregulated by estrogen in the uterus and heart (Liu et al., 2003), by fasting in liver (Ichida et al., 2002) and by cold stress in brown fat and skeletal muscle (Schreiber et al., 2003). The increased ERRα expression during fasting and cold exposure is correlated with the induction of a coactivator, peroxisome-proliferation-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), which is a master regulator in executing the energy metabolism programs (reviewed in Knutti and Kralli, 2001, Puigserver and Spiegelman, 2003). ERRα was identified as a key partner for PGC-1α in regulation of genes involved in the mitochondria oxidative phosphorylation (Huss et al., 2002, Laganiere et al., 2004, Mootha et al., 2004, Schreiber et al., 2003). Interestingly, ERRα itself is PGC-1α inducible (Schreiber et al., 2003). Inhibition of ERRα expression or function compromises the ability of PGC-1α to stimulate genes in mitochondria biogenesis (Huss et al., 2004, Schreiber et al., 2004).