https://ogma.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:31424 Wed 15 Dec 2021 16:08:54 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:6254 Wed 11 Apr 2018 17:53:26 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:21727 EL by protein phosphatase 2A (PP2A). However, melanoma cells are largely resistant to ER stress-induced apoptosis, suggesting that Bim activation is suppressed in melanoma cells undergoing ER stress. We show here that ER stress reduces PP2A activity leading to increased ERK activation and subsequent phosphorylation and proteasomal degradation of Bim_EL. Despite sustained upregulation of Bim at the transcriptional level, the Bim_EL protein expression was downregulated after an initial increase in melanoma cells subjected to pharmacological ER stress. This was mediated by increased activity of ERK, whereas the phosphatase activity of PP2A was reduced by ER stress in melanoma cells. The increase in ERK activation was, at least in part, due to reduced dephosphorylation by PP2A, which was associated with downregulation of the PP2A catalytic C subunit. Notably, instead of direct dephosphorylation of Bim_EL, PP2A inhibited its phosphorylation indirectly through dephosphorylation of ERK in melanoma cells. Taken together, these results identify downregualtion of PP2A activity as an important protective mechanism of melanoma cells against ER stress-induced apoptosis.]]> Wed 11 Apr 2018 17:12:53 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:28327 in vitro we show that inhibition of basal PP2A activity by okadaic acid (OA) releases restraint on MAPKs and thereby increases MAPK-mediated pro-asthmatic cytokines, including IL-6 and IL-8. Notably, PP2A inhibition also impacts on the anti-inflammatory protein – tristetraprolin (TTP), a destabilizing RNA binding protein regulated at multiple levels by p38 MAPK. Although PP2A inhibition increases TTP mRNA expression, resultant TTP protein builds up in the hyperphosphorylated inactive form. Thus, when PP2A activity is repressed, pro-inflammatory cytokines increase and anti-inflammatory proteins are rendered inactive. Importantly, these effects can be reversed by the PP2A activators FTY720 and AAL(s), or more specifically by overexpression of the PP2A catalytic subunit (PP2A-C). Moreover, PP2A plays an important role in cytokine expression in cells stimulated with TNFα; as inhibition of PP2A with OA or PP2A-C siRNA results in significant increases in cytokine production. Collectively, these data reveal the molecular mechanisms of PP2A regulation and highlight the potential of boosting the power of endogenous phosphatases as novel anti-inflammatory strategies to combat asthmatic inflammation.]]> Wed 11 Apr 2018 13:50:35 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:14165 Wed 11 Apr 2018 13:47:17 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:12036 Wed 11 Apr 2018 12:51:04 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:16003 Wed 11 Apr 2018 12:17:35 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:23627 Wed 11 Apr 2018 10:17:52 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33322 Tue 16 Oct 2018 10:02:31 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:41978 Tue 16 Aug 2022 15:48:51 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:27776 Thu 28 Oct 2021 13:04:26 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:41709 Thu 25 Aug 2022 10:06:29 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:36011 Thu 17 Jun 2021 16:06:18 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:41253 Sat 30 Jul 2022 12:54:26 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:1293 Sat 24 Mar 2018 08:32:46 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:2497 1.1, additivity by a CI between 0.9 and 1.1, and synergism by a CI<0.9. Results: Both cell lines were equally sensitive to cantharidin alone (GI50 values 5.4 and 7.3 mgrM), which induced a significant increase in the S-phase population of both cell lines within 6 h with a concomitant increase in DNA synthesis. This response culminated in G2/M cell cycle arrest within 24 h and subsequent cell death. In response to nolatrexed alone, HT29 cells were more sensitive than HCT116 cells (GI50 1.9 mgrM vs 9.8 mgrM), with G1/S-phase cell cycle arrest occurring within 24 h in both cell lines. In HT29 cells, this was followed by cell death, whereas in HCT116 cells, a proportion of cells died following arrest but the predominant event was re-entry into the cell cycle. The simultaneous exposure of HT29 cells to the combination of nolatrexed and cantharidin in drug molar ratios of 1:1 and 1:2.5 for 72 h was synergistic producing composite CIs of 0.88 and 0.87, respectively. The sequence of nolatrexed followed by cantharidin 24 h later resulted in greater synergism (CI values of 0.75, 0.52, 0.55, 0.68 for molar ratios of 10:1, 1:1, 1:2.5, 1:10), whereas the reverse sequence was antagonistic, suggesting that the point of interaction is downstream of TS inhibition. In HCT116 cells only additive and antagonistic interactions were observed for any of the treatment combinations. The lack of synergism in these cells may be caused by the reduced sensitivity of these cells to nolatrexed as a single agent. Conclusion: The effect of TS inhibition can be enhanced by the inhibition of serine/threonine protein phosphatases.]]> Sat 24 Mar 2018 08:27:43 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:10155 Sat 24 Mar 2018 08:07:28 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:21832 Sat 24 Mar 2018 07:58:43 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20150 Sat 24 Mar 2018 07:51:36 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:29786 Tnfsf10^−/−) mice were administered subcutaneous ovalbumin (OVA) followed by oral OVA challenges. In separate experiments, OVA-challenged mice were intraperitoneally administered salmeterol or dexamethasone. Esophageal biopsies from children with EoE revealed increased levels of TRAIL and MID-1 and reduced PP2A activation compared with controls. Tnfsf10^−/− mice were largely protected from esophageal fibrosis, eosinophilic inflammation, and the upregulation of TSLP, IL-5, IL-13, and CCL11 when compared with wild-type mice. Salmeterol administration to wild-type mice with experimental EoE restored PP2A activity and also prevented esophageal eosinophilia, inflammatory cytokine expression, and remodeling, which was comparable to the treatment effect of dexamethasone. TRAIL and PP2A regulate inflammation and fibrosis in experimental EoE, which can be therapeutically modulated by salmeterol.]]> Sat 24 Mar 2018 07:23:39 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:3327 Sat 24 Mar 2018 07:23:19 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:3263 Sat 24 Mar 2018 07:21:22 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:3265 Sat 24 Mar 2018 07:21:21 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:36157 Mon 26 Oct 2020 12:11:15 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:52534 Mon 16 Oct 2023 14:56:57 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:41841 Tnfsf10^−/− BALB/c mice were administered bleomycin to induce fibrosis and some groups were treated with the FTY720 analogue AAL(s) to activate PP2A. Mouse fibroblasts were treated with recombinant TRAIL and fibrotic responses were assessed. Results: TRAIL in serum and MID1 protein levels in biopsies from IPF patients were increased compared to controls. MID1 levels were inversely associated while PP2A activity levels correlated with DLco. Tnfsf10^−/− and mice treated with the PP2A activator AAL(s) were largely protected against bleomycin-induced reductions in lung function and fibrotic changes. Addition of recombinant TRAIL to mouse fibroblasts in-vitro increased collagen production which was reversed by PP2A activation with AAL(s). Conclusion: TRAIL signalling through MID1 deactivates PP2A and promotes fibrosis with corresponding lung function decline. This may provide novel therapeutic targets for IPF.]]> Mon 15 Aug 2022 10:15:38 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:42190 Fri 26 Aug 2022 09:08:16 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:25080 Fri 01 Apr 2022 09:27:01 AEDT ]]>