Search results for: p38β mutant ER
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#29907567 2018/06/15 To Up
Ras signaling activates glycosylphosphatidylinositol (GPI) anchor biosynthesis via the GPI--acetylglucosaminyltransferase (GPI-GnT) in .The ability of to switch between yeast to hyphal form is a property that is primarily associated with the invasion and virulence of this human pathogenic fungus. Several glycosylphosphatidylinositol (GPI)-anchored proteins are expressed only during hyphal morphogenesis. One of the major pathways that controls hyphal morphogenesis is the Ras-signaling pathway. We examine the cross-talk between GPI anchor biosynthesis and Ras signaling in We show that the first step of GPI biosynthesis is activated by Ras in This is diametrically opposite to what is reported in Of the two Ras proteins, CaRas1 alone activates GPI-GnT activity; activity is further stimulated by constitutively activated CaRas1. CaRas1 localized to the cytoplasm or endoplasmic reticulum (ER) is sufficient for GPI-GnT activation. Of the six subunits of the GPI--acetylglucosaminyltransferase (GPI-GnT) that catalyze the first step of GPI biosynthesis, CaGpi2 is the key player involved in activating Ras signaling and hyphal morphogenesis. Activation of Ras signaling is independent of the catalytic competence of GPI-GnT. This too is unlike what is observed in where multiple subunits were identified as inhibiting Ras2. Fluorescence resonance energy transfer (FRET) studies indicate a specific physical interaction between CaRas1 and CaGpi2 in the ER, which would explain the ability of CaRas1 to activate GPI-GnT. CaGpi2, in turn, promotes activation of the Ras-signaling pathway and hyphal morphogenesis. The mutant is also more susceptible to macrophage-mediated killing, and macrophage cells show better survival when co-cultured with .
Priyanka Jain, Subhash Chandra Sethi, Vavilala A Pratyusha, Pramita Garai, Nilofer Naqvi, Sonali Singh, Kalpana Pawar, Niti Puri, Sneha Sudha Komath
1136 related Products with: Ras signaling activates glycosylphosphatidylinositol (GPI) anchor biosynthesis via the GPI--acetylglucosaminyltransferase (GPI-GnT) in .100 μg2 Pieces/Box11 inhibitors2 Pieces/Box100 μg2 Pieces/Box1 Set12 Pieces/Box
#29855477 2018/05/31 To Up
Inhibition of the ER stress IRE1α inflammatory pathway protects against cell death in mitochondrial complex I mutant cells.Mitochondrial mutations cause bioenergetic defects associated with failures to use the electron transfer chain and oxidize substrates. These defects are exacerbated under energetic stress conditions and ultimately cause cell deterioration and death. However, little is known about cellular strategies that rescue mitochondrial stress failures and maintain cell survival under these conditions. Here, we have designed and performed a high-throughput chemical screen to identify small molecules that rescue human mitochondrial complex I mutations from energetic stress-induced cell death. The top positive hits were a series of sulfonylureas that efficiently maintain prolonged cell survival and growth under energetic stress conditions. The addition of galactose instead of glucose, to experimentally force mitochondrial respiration, triggered an initial ER stress response that was associated with IRE1α-dependent inflammatory signals including JNK and p38 MAP kinases in mutant cells. Sulfonylureas, similar to inhibition of IRE1α and p38 MAP kinase, potently blocked this ER stress inflammatory and cell death pathway and maintained viability and cell growth under severe energetic stress conditions. These studies reveal that sulfonylureas and specific inhibition of the IRE1α inflammatory pathway protect against cell death and can be used to rescue bioenergetic failures in mitochondrial complex I-mutated cells under stress conditions.
Meghan S Soustek, Eduardo Balsa, Joeva J Barrow, Mark Jedrychowski, Rutger Vogel, Jan Smeitink, Steve P Gygi, Pere Puigserver
1066 related Products with: Inhibition of the ER stress IRE1α inflammatory pathway protects against cell death in mitochondrial complex I mutant cells.100ug Lyophilized2 Pieces/Box100ug Lyophilized100 µg100ug Lyophilized2 Pieces/Box1.00 flask96 tests100ug Lyophilized1x10e7 cells-100ug Lyophilized
#29027919 2017/10/13 To Up
Shiga Toxins Induce Apoptosis and ER Stress in Human Retinal Pigment Epithelial Cells.Shiga toxins (Stxs) produced by Shiga toxin-producing bacteria serotype 1 and select serotypes of are the most potent known virulence factors in the pathogenesis of hemorrhagic colitis progressing to potentially fatal systemic complications such as acute renal failure, blindness and neurological abnormalities. Although numerous studies have defined apoptotic responses to Shiga toxin type 1 (Stx1) or Shiga toxin type 2 (Stx2) in a variety of cell types, the potential significance of Stx-induced apoptosis of photoreceptor and pigmented cells of the eye following intoxication is unknown. We explored the use of immortalized human retinal pigment epithelial (RPE) cells as an in vitro model of Stx-induced retinal damage. To the best of our knowledge, this study is the first report that intoxication of RPE cells with Stxs activates both apoptotic cell death signaling and the endoplasmic reticulum (ER) stress response. Using live-cell imaging analysis, fluorescently labeled Stx1 or Stx2 were internalized and routed to the RPE cell endoplasmic reticulum. RPE cells were significantly sensitive to wild type Stxs by 72 h, while the cells survived challenge with enzymatically deficient mutant toxins (Stx1A or Stx2A). Upon exposure to purified Stxs, RPE cells showed activation of a caspase-dependent apoptotic program involving a reduction of mitochondrial transmembrane potential (Δψ), increased activation of ER stress sensors IRE1, PERK and ATF6, and overexpression CHOP and DR5. Finally, we demonstrated that treatment of RPE cells with Stxs resulted in the activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), suggesting that the ribotoxic stress response may be triggered. Collectively, these data support the involvement of Stx-induced apoptosis in ocular complications of intoxication. The evaluation of apoptotic responses to Stxs by cells isolated from multiple organs may reveal unique functional patterns of the cytotoxic actions of these toxins in the systemic complications that follow ingestion of toxin-producing bacteria.
Jun-Young Park, Yu-Jin Jeong, Sung-Kyun Park, Sung-Jin Yoon, Song Choi, Dae Gwin Jeong, Su Wol Chung, Byung Joo Lee, Jeong Hun Kim, Vernon L Tesh, Moo-Seung Lee, Young-Jun Park
1923 related Products with: Shiga Toxins Induce Apoptosis and ER Stress in Human Retinal Pigment Epithelial Cells.100 μg10 ug50 ul4 Membranes/Box 100ul1.00 flask5ug1.00 flask100 100 ul1.00 flask1.00 flask
#28471037 2017/05/31 To Up
Oxysterol-binding protein recruitment and activity at the endoplasmic reticulum-Golgi interface are independent of Sac1.Oxysterol-binding protein (OSBP) localizes to endoplasmic reticulum (ER)-Golgi contact sites where it transports cholesterol and phosphatidylinositol 4-phosphate (PI-4P), and activates lipid transport and biosynthetic activities. The PI-4P phosphatase Sac1 cycles between the ER and Golgi apparatus where it potentially regulates OSBP activity. Here we examined whether the ER-Golgi distribution of endogenous or ectopically expressed Sac1 influences OSBP activity. OSBP and Sac1 co-localized at apparent ER-Golgi contact sites in response to 25-hydroxycholesterol (25OH), cholesterol depletion and p38 MAPK inhibitors. A Sac1 mutant that is unable to exit the ER did not localize with OSBP, suggesting that sterol perturbations cause Sac1 transport to the Golgi apparatus. Ectopic expression of Sac1 in the ER or Golgi apparatus, or Sac1 silencing, did not affect OSBP localization to ER-Golgi contact sites, OSBP-dependent activation of sphingomyelin synthesis, or cholesterol esterification in the ER. p38 MAPK inhibition and retention of Sac1 in the Golgi apparatus also caused OSBP phosphorylation and OSBP-dependent activation of sphingomyelin synthesis at ER-Golgi contacts. These results demonstrate that Sac1 expression in either the ER or Golgi apparatus has a minimal impact on the PI-4P that regulates OSBP activity or recruitment to contact sites.
Mark Charman, Asako Goto, Neale D Ridgway
2000 related Products with: Oxysterol-binding protein recruitment and activity at the endoplasmic reticulum-Golgi interface are independent of Sac1.1000 TESTS/0.65ml 100ul1 mg5 x 200 ug501mg100ul220 μg0.2 mg1 kit(96 Wells)96T
#28433684 2017/04/19 To Up
Activating transcription factor 6-dependent sestrin 2 induction ameliorates ER stress-mediated liver injury.Endoplasmic reticulum (ER) stress is characterized by an accumulation of misfolded proteins, and ER stress reduction is essential for maintaining tissue homeostasis. However, the molecular mechanisms that protect cells from ER stress are not completely understood. The present study investigated the role of sestrin 2 (SESN2) on ER stress and sought to elucidate the mechanism responsible for the hepatoprotective effect of SESN2 in vitro and in vivo. Treatment with tunicamycin (Tm) increased SESN2 protein and mRNA levels and reporter gene activity. Activating transcription factor 6 (ATF6) bound to unfolded protein response elements of SESN2 promoter, transactivated SESN2, and increased SESN2 protein expression. In addition, dominant negative mutant of ATF6α and siRNA against ATF6α blocked the ER stress-mediated SESN2 induction, whereas chemical inhibition of PERK or IRE1 did not affect SESN2 induction by Tm. Ectopic expression of SESN2 in HepG2 cells inhibited CHOP and GRP78 expressions by Tm. Moreover, SESN2 decreased the phosphorylations of JNK and p38 and PARP cleavage, and blocked the cytotoxic effect of excessive ER stress. In a Tm-induced liver injury model, adenoviral delivery of SESN2 in mice decreased serum ALT, AST and LDH activities and the mRNA levels of CHOP and GRP78 in hepatic tissues. Moreover, SESN2 reduced numbers of degenerating hepatocytes, and inhibited caspase 3 and PARP cleavages. These results suggest ATF6 is essential for ER stress-mediated SESN2 induction, and that SESN2 acts as a feedback regulator to protect liver from excess ER stress.
Kyung Hwan Jegal, Sang Mi Park, Sam Seok Cho, Sung Hui Byun, Sae Kwang Ku, Sang Chan Kim, Sung Hwan Ki, Il Je Cho
1980 related Products with: Activating transcription factor 6-dependent sestrin 2 induction ameliorates ER stress-mediated liver injury.200ug200ug200ug200ug6 25UG500ug100 ug250ul1 g250ul250ul
#27714068 // To Up
A systems biology approach reveals new endoplasmic reticulum-associated targets for the correction of the ATP7B mutant causing Wilson disease.Copper (Cu) is an important trace element required for the activity of essential enzymes. However, excess Cu compromises the redox balance in cells and tissues causing serious toxicity. The process of disposal of excess Cu from organisms relies on the activity of Cu-transporting ATPase ATP7B. ATP7B is mainly expressed in liver hepatocytes where it sequesters the potentially toxic metal and mediates its excretion into the bile. Mutations in the ATP7B gene cause Wilson disease (WD), which is characterized by the accumulation of toxic Cu in the liver due to the scarce expression of ATP7B as well as the failure of ATP7B mutants to pump Cu and/or traffic to the Cu-excretion sites. The most frequent ATP7B mutant, H1069Q, still presents a significant Cu-transporting activity, but undergoes retention within the endoplasmic reticulum (ER) where the mutant is rapidly degraded. Expression of this ATP7B mutant has been recently reported to activate the p38 and JNK stress kinase pathways, which, in turn, trigger quality control mechanisms leading to the arrest of ATP7B-H1069Q in the ER and to the acceleration of its degradation. However, the main molecular players operating in these p38/JNK-dependent ER quality control pathways remain to be discovered. By using a combination of RNAseq, bioinformatics and RNAi approaches, we found a cluster of ER quality control genes whose expression is controlled by p38 and JNK and is required for the efficient retention of the ATP7B-H1069Q mutant in the ER. Silencing these genes reduced the accumulation of the ATP7B mutant in the ER and facilitated the mutant sorting and export to the Golgi and post-Golgi copper excretion sites. In sum, our findings reveal the ER-associated genes that could be utilized for the correction of ATP7B mutants and, hence, for the normalization of Cu homeostasis in Wilson disease.
Mafalda Concilli, Simona Iacobacci, Giancarlo Chesi, Annamaria Carissimo, Roman Polishchuk
1823 related Products with: A systems biology approach reveals new endoplasmic reticulum-associated targets for the correction of the ATP7B mutant causing Wilson disease.0.1 mg100.00 ul1 mg 100ul100.00 ul
#27448221 2016/07/22 To Up
Enhancement of hyperthermia-induced apoptosis by 5Z-7-oxozeaenol, a TAK1 inhibitor, in A549 cells.KRAS mutant lung cancers have long been considered as untreatable with drugs. Transforming growth factor-β-activated kinase 1 (TAK1) appears to play an anti-apoptotic role in response to multiple stresses and has been reported to be a responsive kinase that regulates cell survival in KRAS-dependent cells. In this study, in order to find a useful approach to treat KRAS mutant lung cancer, we focused on the combined effects of 5Z-7-oxozeaenol, a TAK1 inhibitor, with hyperthermia (HT) in KRAS mutant lung cancer cell line A549. Annexin V-FITC/PI assay, cell cycle analysis, and colony formation assay revealed a significant enhancement in apoptosis induced by HT treatment, when the cells were pre-incubated with 5Z-7-oxozeaenol in a dose-dependent manner. The enhanced apoptosis by 5Z-7-oxozeaenol was accompanied by a significant increase in reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential (MMP). In addition, western blot showed that 5Z-7-oxozeaenol enhanced HT-induced expressions of cleaved caspase-3, cleaved caspase-8, and HSP70 and decreased HT-induced expressions of Bcl-2, p-p38, p-JNK, and LC3. Moreover, 5Z-7-oxozeaenol pre-treatment resulted in a marked elevation of intracellular calcium level which might be associated with endoplasmic reticulum (ER) stress-related pathway. Taken together, our data provides further insights of the mechanism of action of 5Z-7-oxozeaenol and HT treatment, and their potential application as a novel approache to treat patients with KRAS mutant lung cancer.
Peng Li, Qing-Li Zhao, Paras Jawaid, Mati Ur Rehman, Hiroaki Sakurai, Takashi Kondo
1768 related Products with: Enhancement of hyperthermia-induced apoptosis by 5Z-7-oxozeaenol, a TAK1 inhibitor, in A549 cells.100 20 µl (10 mM)100ug Lyophilized100 100 2 mg20 4 Arrays/Slide100 10mg100 100
#27117504 2016/04/27 To Up
Secretory pathway retention of mutant prion protein induces p38-MAPK activation and lethal disease in mice.Misfolding of proteins in the biosynthetic pathway in neurons may cause disturbed protein homeostasis and neurodegeneration. The prion protein (PrP(C)) is a GPI-anchored protein that resides at the plasma membrane and may be misfolded to PrP(Sc) leading to prion diseases. We show that a deletion in the C-terminal domain of PrP(C) (PrPΔ214-229) leads to partial retention in the secretory pathway causing a fatal neurodegenerative disease in mice that is partially rescued by co-expression of PrP(C). Transgenic (Tg(PrPΔ214-229)) mice show extensive neuronal loss in hippocampus and cerebellum and activation of p38-MAPK. In cell culture under stress conditions, PrPΔ214-229 accumulates in the Golgi apparatus possibly representing transit to the Rapid ER Stress-induced ExporT (RESET) pathway together with p38-MAPK activation. Here we describe a novel pathway linking retention of a GPI-anchored protein in the early secretory pathway to p38-MAPK activation and a neurodegenerative phenotype in transgenic mice.
Berta Puig, Hermann C Altmeppen, Sarah Ulbrich, Luise Linsenmeier, Susanne Krasemann, Karima Chakroun, Claudia Y Acevedo-Morantes, Holger Wille, Jörg Tatzelt, Markus Glatzel
2417 related Products with: Secretory pathway retention of mutant prion protein induces p38-MAPK activation and lethal disease in mice.1 Set100 μg1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set1 Set
#26733232 2015/12/17 To Up
AGR2 oncoprotein inhibits p38 MAPK and p53 activation through a DUSP10-mediated regulatory pathway.The tumor suppressor p53 plays a key role in malignant transformation and tumor development. However, the frequency of p53 mutations within individual types of cancer is different, suggesting the existence of other mechanisms attenuating p53 tumor suppressor activity. Changes in upstream regulators of p53 such as MDM2 amplification and overexpression, expression of viral oncoproteins, estrogen receptor signaling, or changes in p53 transcriptional target genes were previously described in wild-type p53 tumors. We identified a novel pathway responsible for attenuation of p53 activity in human cancers. We demonstrate that AGR2, which is overexpressed in a variety of human cancers and provides a poor prognosis, up-regulates DUSP10 which subsequently inhibits p38 MAPK and prevents p53 activation by phosphorylation. Analysis of human breast cancers reveals that AGR2 specifically provides a poor prognosis in ER+ breast cancers with wild-type p53 but not ER- or mutant p53 breast cancers, and analysis of independent data sets show that DUSP10 levels also have prognostic significance in this specific sub-group of patients. These data not only reveal a novel pro-oncogenic signaling pathway mediating resistance to DNA damaging agents in human tumors, but also has implications for designing alternative strategies for modulation of wild-type p53 activity in cancer therapy.
Roman Hrstka, Pavla Bouchalova, Eva Michalova, Eva Matoulkova, Petr Muller, Philip J Coates, Borivoj Vojtesek
1767 related Products with: AGR2 oncoprotein inhibits p38 MAPK and p53 activation through a DUSP10-mediated regulatory pathway.100ug100ug2 Pieces/Box100ug100ug Lyophilized100ug2 Pieces/Box100ug100ug100ug Lyophilized100ug100ug
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