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Pro-survival Factors (pro-survival + factor)
Selected AbstractsORIGINAL ARTICLE: Antiphospholipid Antibodies Induce a Pro-Inflammatory Response in First Trimester Trophoblast Via the TLR4/MyD88 PathwayAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2009Melissa J. Mulla Problem, Women with antiphospholipid antibodies (aPL) are at risk for recurrent miscarriage, pre-eclampsia, and pre-term labor. aPL target the placenta directly by binding to beta2 -glycoprotein I (,2GPI) expressed on the surface of trophoblast cells. The objective of this study was to determine the effects of aPL on trophoblast function and the mechanisms involved. Method of study, First trimester trophoblast cells were treated with anti-,2GPI monoclonal antibodies and patient-derived aPL, after which cell survival and function was evaluated. Results, We report that anti-,2GPI antibodies trigger an inflammatory response in trophoblast, characterized by increased secretion of interleukin (IL)-8, MCP-1, GRO-,, and IL-1,, and that this occurs in a TLR-4/MyD88-dependent manner. At high concentrations, these antibodies also induce caspase-mediated cell death. This was attenuated upon disabling of the MyD88 pathway, suggesting that anti-,2GPI-induced inflammatory mediators compromise trophoblast survival by acting in an autocrine/paracrine manner. Enhanced IL-8, GRO-,, and IL-1, secretion also occurred when trophoblast cells were incubated with antibodies from patients with antiphospholipid syndrome. Heparin, which acts as a pro-survival factor in human trophoblast, attenuated the anti-,2GPI antibody-mediated cell death, and also the pro-inflammatory response, but only at high concentrations. Conclusion, These findings demonstrate that aPL triggers a placental inflammatory response via the TLR-4/MyD88 pathway, which in turn compromises trophoblast survival. Thus, the TLR-4/MyD88 pathway may provide a new therapeutic target to improve pregnancy outcome in antiphospholipid syndrome patients. [source] Pituitary adenylate cyclase-activating polypeptide attenuates streptozotocin-induced apoptotic death of RIN-m5F cells through regulation of Bcl-2 family protein mRNA expressionFEBS JOURNAL, Issue 22 2008Satomi Onoue Oxidative stress, followed by the apoptotic death of pancreatic , cells, is considered to be one of causative agents in the evolution of the type 2 diabetic state; therefore, the protection of , cells can comprise an efficacious strategy for preventing type 2 diabetes. In the present study, RIN-m5F cells (i.e. the rat insulinoma , cell line) were stimulated with streptozotocin, resulting in a time- and concentration-dependent release of lactate dehydrogenase. There appeared to be significant apoptotic cell death after 2 h of treatment with streptozotocin at 10 mm, as demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining and 2.6-fold activation of cellular caspase-3, an apoptotic enzyme. By contrast, some neuropeptides of the glucagon-secretin family and coenzyme Q10, an endogenous mitochondrial antioxidant, could attenuate streptozotocin cytotoxicity, and especially pituitary adenylate cyclase-activating polypeptide (PACAP), at a concentration of 10,7 m, exhibited 34% attenuation of lactate dehydrogenase release from streptozotocin-treated RIN-m5F cells. Quantitative RT-PCR experiments indicated the inhibitory effect of PACAP on streptozotocin-evoked up-regulation of pro-apoptotic factor (Noxa and Bax) and a 2.3-fold enhancement of Bcl-2 mRNA expression, a pro-survival protein, was also observed after addition of PACAP. The data obtained suggest the anti-apoptotic role of PACAP in streptozotocin-treated RIN-m5F cells through the regulation of pro-apoptotic and pro-survival factors. [source] Shepherding AKT and androgen receptor by Ack1 tyrosine kinaseJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2010Kiran Mahajan Ack1 (also known as ACK, TNK2, or activated Cdc42 kinase) is a structurally unique non-receptor tyrosine kinase that is expressed in diverse cell types. It integrates signals from plethora of ligand-activated receptor tyrosine kinases (RTKs), for example, MERTK, EGFR, HER2, PDGFR and insulin receptor to initiate intracellular signaling cascades. Ack1 transduces extracellular signals to cytosolic and nuclear effectors such as the protein kinase AKT/PKB and androgen receptor (AR), to promote cell survival and growth. While tyrosine phosphorylation of AR at Tyr267 regulates androgen-independent recruitment of AR to the androgen-responsive enhancers and transcription of AR target genes to drive prostate cancer progression, phosphorylation of an evolutionarily conserved Tyrosine 176 in the kinase domain of AKT is essential for mitotic progression and positively correlates with breast cancer progression. In contrast to AR and AKT, Ack1-mediated phosphorylation of the tumor suppressor Wwox at Tyr287 lead to rapid Wwox polyubiquitination followed by degradation. Thus, by its ability to promote tumor growth by negatively regulating tumor suppressor such as Wwox and positively regulating pro-survival factors such as AKT and AR, Ack1 is emerging as a critical player in cancer biology. In this review, we discuss recent advances in understanding the physiological functions of Ack1 signaling in normal cells and the consequences of its hyperactivation in various cancers. J. Cell. Physiol. 224: 327,333, 2010. © 2010 Wiley-Liss, Inc. [source] Dysfunction of the unfolded protein response increases neurodegeneration in aged rat hippocampus following proteasome inhibitionAGING CELL, Issue 6 2009María Paz Gavilán Summary Dysfunctions of the ubiquitin proteasome system (UPS) have been proposed to be involved in the aetiology and/or progression of several age-related neurodegenerative disorders. However, the mechanisms linking proteasome dysfunction to cell degeneration are poorly understood. We examined in young and aged rat hippocampus the activation of the unfolded protein response (UPR) under cellular stress induced by proteasome inhibition. Lactacystin injection blocked proteasome activity in young and aged animals in a similar extent and increased the amount of ubiquitinated proteins. Young animals activated the three UPR arms, IRE1,, ATF6, and PERK, whereas aged rats failed to induce the IRE1, and ATF6, pathways. In consequence, aged animals did not induce the expression of pro-survival factors (chaperones, Bcl-XL and Bcl-2), displayed a more sustained expression of pro-apoptotic markers (CHOP, Bax, Bak and JKN), an increased caspase-3 processing. At the cellular level, proteasome inhibition induced neuronal damage in young and aged animals as assayed using Fluorojade-B staining. However, degenerating neurons were evident as soon as 24 h postinjection in aged rats, but it was delayed up to 3 days in young animals. Our findings show evidence supporting age-related dysfunctions in the UPR activation as a potential mechanism linking protein accumulation to cell degeneration. An imbalance between pro-survival and pro-apoptotic proteins, because of noncanonical activation of the UPR in aged rats, would increase the susceptibility to cell degeneration. These findings add a new molecular vision that might be relevant in the aetiology of several age-related neurodegenerative disorders. [source] |