Zinc Pyrithione of Then the mechanisms responsible for BPA i
Then the mechanisms responsible for BPA induced up regulation of ERRγ were further investigated. Recent studies indicated that Akt and MPAK can modulate the protein levels and transcriptional activities of ERRγ (Heckler et al., 2014, Sun et al., 2014). Previous studies also indicated that BPA can activate MAPK in various Zinc Pyrithione of (Ptak and Gregoraszczuk, 2012, Pupo et al., 2012). Therefore the roles of MAPK in BPA induced ERRγ expression were investigated. We found that BPA significantly activated ERK1/2 while not JNK or p-38 MAPK. Furthermore, PD 98059, the inhibitor of ERK1/2, significantly abolished BPA induced up regulation of ERRγ and proliferation of breast cancer cells. This was consistent with the previous study that all three members of the MAPK family (ERK, JNK, p38) phosphorylate the same S–P core motif (Heckler et al., 2014), but our data show that only pharmacological inhibition of ERK reduces ERRγ protein levels in breast cancer cells. It was suggested that ERK1/2 can increase the transcriptional activities of ERRγ by modulating the phosphorylation of ERRγ at three serine residues (Heckler et al., 2014). Whether the nuclear translocation of ERRγ induced by BPA is mediated by the phosphorylation still needs further studies.
Conflicts of interest
Acknowledgments This work was supported by National Natural Science Foundation of China (grant no. 81301919 and 81301854), Scientific Research Foundation of the Education Department of Sichuan Province (grant no. 14ZA0230), and Natural Science Foundation of Chengdu Medical College (grant no. 13Z092), and all support is gratefully acknowledged.
Introduction In healthy individuals, pancreatic β cells secrete insulin in response to nutrients such as glucose, amino acids, and free fatty acids to regulate blood glucose levels and lipid metabolism (Prentki et al., 2013), whereas β cell failure or impaired function is associated with both type 1 and type 2 diabetes (Ashcroft and Rorsman, 2012). The continuing challenges in treating diabetes placed the development of transplantable β cells as one of the central goals of stem cell therapy. While human embryonic and pluripotent stem cells (hESCs and hPSCs) offer this potential, it has been difficult to realize this therapeutic promise. The recent descriptions of embryonic stem-derived β-like cells reflect both the progress and ongoing challenges in achieving functionally mature β cells in vitro (Pagliuca et al., 2014, Rezania et al., 2014). Interestingly, transplantation of these pre-functional cells into mice results in a progressive in vivo maturation, presumably facilitated by the complex internal milieu reflecting a process that may be too complex to achieve in cell culture. β cells are known to facilitate glucose-stimulated insulin secretion (GSIS) through increased mitochondrial oxidative ATP production (Prentki et al., 2013, Supale et al., 2012). Whereas the cellular components required for GSIS are well established, the key transcriptional networks that regulate β cell metabolism and insulin secretion remain poorly understood. Nuclear receptors are ligand-dependent transcription factors that play central roles in controlling development, growth, and metabolism (Evans and Mangelsdorf, 2014). Estrogen-related receptors (ERRs) are orphan nuclear receptors represented by three paralogs in mammals, ERRα (NR3B1, Esrra), ERRβ (NR3B2, Esrrb), and ERRγ (NR3B3, Esrrg). ERRβ is known to play an essential role in embryonic stem cell maintenance (Feng et al., 2009, Festuccia et al., 2012) whereas ERRα and ERRγ regulate oxidative pathways such as the tricarboxylic acid cycle, the electron transport complex (ETC), and oxidative phosphorylation (OxPhos). Notably, genetic studies in mice have revealed distinct functions for ERRα and ERRγ (Alaynick et al., 2007, Dufour et al., 2007, Luo et al., 2003). While whole body ERRα knockout (ERRαKO) mice are developmentally normal, they are lean and resistant to high fat diet-induced obesity (Luo et al., 2003). In contrast, whole body ERRγ knockout (ERRγKO) mice have significant developmental abnormalities and marked postnatal lethality attributed to defects in energy utilization, severely limiting their experimental utility (Alaynick et al., 2007).