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Youming Ding, Xiaoyan Chen, Bin Wang, Bin Yu, Jianhui Ge
b-AP15, a potent and selective inhibitor of the ubiquitin-specific peptidase 14 (USP14), displays in vitro and in vivo antitumor abilities on some types of cancer cells. However, the mechanism underlying its action is not well elucidated. The purposes of the present study are to observe the potential impacts of b-AP15 on cell survival of hepatocellular carcinoma cells and to investigate whether and how this compound inhibits some survival-promoting signaling pathways. We found that b-AP15 significantly decreased cell viability and increased cell apoptosis in a dose-dependent manner in hepatocellular carcinoma cells, along with the perturbation of cell cycle and the decreased expressions of cell cycle-related proteins...
February 15, 2018: European Journal of Pharmacology
Timothy J Bergmann, Ilaria Fregno, Fiorenza Fumagalli, Andrea Rinaldi, Francesco Bertoni, Paul J Boersema, Paola Picotti, Maurizio Molinari
The stress sensors ATF6, IRE1 and PERK monitor deviations from homeostatic conditions in the endoplasmic reticulum (ER), a protein biogenesis compartment of eukaryotic cells. Their activation elicits unfolded protein responses (UPR) to re-establish proteostasis. UPR have been extensively investigated in cells exposed to chemicals that activate ER stress sensors by perturbing calcium, N-glycans or redox homeostasis. Cell responses to variations in luminal load with unfolded proteins are, in contrast, poorly characterized...
February 16, 2018: Journal of Biological Chemistry
Chi Thanh Mai, Quynh Giang Le, Yuki Ishiwata-Kimata, Hiroshi Takagi, Kenji Kohno, Yukio Kimata
Accumulation of unfolded secretory proteins in the endoplasmic reticulum (ER), namely ER stress, is hazardous to eukaryotic cells and promotes the unfolded protein response (UPR). Ire1 is an ER-located transmembrane protein that senses ER stress and triggers the UPR. According to previous in vitro experiments, 4-phenylbutyrate (4-PBA) works as a chemical molecular chaperone. Since 4-PBA attenuates the UPR in mammalian tissue cultures, this chemical may have clinical potential for restoring ER-stressing conditions...
February 14, 2018: FEMS Yeast Research
Richard H Chapple, Tianyuan Hu, Yu-Jung Tseng, Lu Liu, Ayumi Kitano, Victor Luu, Kevin A Hoegenauer, Takao Iwawaki, Qing Li, Daisuke Nakada
Activation of the unfolded protein response (UPR) sustains protein homeostasis (proteostasis) and plays a fundamental role in tissue maintenance and longevity of organisms. Long-range control of UPR activation has been demonstrated in invertebrates, but such mechanisms in mammals remain elusive. Here, we show that the female sex hormone estrogen regulates the UPR in hematopoietic stem cells (HSCs). Estrogen treatment increases the capacity of HSCs to regenerate the hematopoietic system upon transplantation and accelerates regeneration after irradiation...
February 16, 2018: ELife
Carrie R Sowers, Rong Wang, Rebecca A Bourne, Barbara C McGrath, Jingjie Hu, Sarah C Bevilacqua, James C Paton, Adrienne W Paton, Sophie Collardeau-Frachon, Marc Nicolino, Douglas R Cavener
Loss-of-function mutations of the protein kinase PERK (EIF2AK3) in humans and mice cause permanent neonatal diabetes and severe proinsulin aggregation in the endoplasmic reticulum (ER), highlighting the essential role of PERK in insulin production in pancreatic β cells. As PERK is generally known as a translational regulator of the Unfolded Protein Response (UPR), the underlying cause of these β cell defects has often been attributed to derepression of proinsulin synthesis, resulting in proinsulin overload in the ER...
February 14, 2018: Journal of Biological Chemistry
Jia-Min Zhang, Xiao-Lu Zhu, Jing Xue, Xiao Liu, X Long Zheng, Ying-Jun Chang, Kai-Yan Liu, Xiao-Jun Huang, Xiao-Hui Zhang
Our understanding of the pathogenesis of immune thrombocytopenia (ITP) remains limited due to the complexity and heterogeneity of the disease. Recently, we observed that bone marrow mesenchymal stem cells (MSCs) derived from ITP patients exhibited growth defects and functional abnormalities that might be involved in the breakdown of self-tolerance. However, the underlying mechanism remains unclear. In this study, we profiled the expression of both mRNAs and miRNAs by utilizing the microarray technique and deciphered the mechanism underlying the impairment of MSCs derived from ITP patients (MSC-ITP)...
February 13, 2018: Functional & Integrative Genomics
Zhifen Yang, Jing Zhang, Dadi Jiang, Purvesh Khatri, David E Solow-Cordero, Diego A S Toesca, Constantinos Koumenis, Nicholas C Denko, Amato J Giaccia, Quynh-Thu Le, Albert C Koong
Activation of the unfolded protein response (UPR) signaling pathways is linked to multiple human diseases including cancer. The inositol-requiring kinase 1 (IRE1)-X-box binding protein 1 (XBP1) pathway is the most evolutionarily conserved of the three major signaling branches of the UPR. Here, we performed a genome-wide siRNA screen to obtain a systematic assessment of genes integrated in the IRE1-XBP1 axis. We monitored the expression of an XBP1-luciferase chimeric protein in which luciferase was fused in-frame with the spliced (active) form of XBP1...
February 9, 2018: Molecular Cancer Research: MCR
Chiara Lanzillotta, Antonella Tramutola, Shelby Meier, Frederick Schmitt, Eugenio Barone, Marzia Perluigi, Fabio Di Domenico, Jose F Abisambra
Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. DS individuals have an increased risk of developing Alzheimer's disease (AD)-like pathology and dementia by the age of 40 due to the triplication of several genes involved in the formation of amyloid plaques and tau tangles. Further, DS and AD are characterized by the aberrant accumulation of unfolded/misfolded proteins resulting from over-burdened protein quality control systems...
2018: Journal of Alzheimer's Disease: JAD
Nurulain Ho, Chengchao Xu, Guillaume Thibault
The unfolded protein response (UPR) is classically viewed as a stress response pathway to maintain protein homeostasis at the endoplasmic reticulum (ER). However, it has recently emerged that the UPR can be directly activated by lipid perturbation, independently of misfolded proteins. Comprising primarily phospholipids, sphingolipids and sterols, individual membranes can contain hundreds of distinct lipids. Even with such complexity, lipid distribution in a cell is tightly regulated by mechanisms that remain incompletely understood...
February 8, 2018: Journal of Cell Science
Sarrabeth Stone, Shuangchan Wu, Stephanie Jamison, Wilaiwan Durose, Jean Pierre Pallais, Wensheng Lin
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play a critical role in immune-mediated demyelinating diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), by regulating the viability of oligodendrocytes. Our previous studies show that activation of the PERK branch of the UPR protects myelinating oligodendrocytes against ER stress in young, developing mice that express IFN-γ, a key pro-inflammatory cytokine in MS and EAE, in the CNS...
February 13, 2018: Glia
Shengwei Jiang, Yuchun Lin, Huan Yao, Chuanli Yang, Liyin Zhang, Bing Luo, Zhao Lei, Liwei Cao, Naibo Lin, Xiangyang Liu, Zhongning Lin, Chengyong He
Unfolded protein response (UPR) and endoplasmic reticulum (ER)-phagy are essential for cell homeostasis. Quantum dots (QDs), which have been widely used for biomedical applications, can accumulate in the kidney tissues and may cause renal dysfunction. However, the molecular mechanism of QDs-induced nephrotoxicity is still obscure. The present study was aimed to elucidate the role and mechanism of UPR and ER-phagy in QDs-induced nephrotoxicity. Herein, human embyronic kidney (HEK) cells were exposed to 15, 30, 45, and 60 nM cadmium telluride (CdTe)-QDs for 12 and 24 h...
February 12, 2018: Archives of Toxicology
Dong Zhou, Fei-Jie Zhi, Mao-Zhen Qi, Fu-Rong Bai, Guangdong Zhang, Jun-Mei Li, Huan Liu, Hua-Tao Chen, Peng-Fei Lin, Ke-Qiong Tang, Wei Liu, Ya-Ping Jin, Ai-Hua Wang
Brucella is an intracellular bacterium that causes the zoonosis brucellosis worldwide. Alveolar macrophages (AM) constitute the main cell target of inhaled Brucella. Brucella thwarts immune surveillance and evokes endoplasmic reticulum (ER) stress to replicate in macrophages via virulence factors. The GntR regulators family was concentrated as an important virulence factor in controlling virulence and intracellular survival of Brucella. However, the detailed underlying mechanism for the host-pathogen interaction is poorly understood...
January 12, 2018: Oncotarget
Besio Roberta, Iula Giusy, Garibaldi Nadia, Cipolla Lina, Sabbioneda Simone, Biggiogera Marco, C Marini Joan, Rossi Antonio, Forlino Antonella
The clinical phenotype in osteogenesis imperfecta (OI) is attributed to the dominant negative function of mutant type I collagen molecules in the extracellular matrix, by altering its structure and function. Intracellular retention of mutant collagen has also been reported, but its effect on cellular homeostasis is less characterized. Using OI patient fibroblasts carrying mutations in the α1(I) and α2(I) chains we demonstrate that retained collagen molecules are responsible for endoplasmic reticulum (ER) enlargement and activation of the unfolded protein response (UPR) mainly through the eukaryotic translation initiation factor 2 alpha kinase 3 (PERK) branch...
February 9, 2018: Biochimica et Biophysica Acta
Shinichi Yonekura, Megumi Tsuchiya, Yukako Tokutake, Moeko Mizusawa, Miwa Nakano, Makoto Miyaji, Hiroshi Ishizaki, Satoshi Haga
The unfolded protein response (UPR) describes a process involved in the homeostasis of endoplasmic reticulum (ER) and the differentiation of secretory cells. At present, the roles of UPR in the mammary gland tissue of dairy cattle are unknown. In the current study, we investigated the expression of UPR-related genes in Holstein cows during the developmental and lactating stages of the mammary gland tissue. To investigate the roles of UPR during the differentiation of mammary epithelial cells (MEC), we used MAC-T cells, a line of MEC...
February 7, 2018: Journal of Dairy Science
Sen Xu, Wen-Ying Liu, Fei-Fei Zhao, You-Jie Li, Zhen Yue, Fei Jiao, Shu-Yang Xie
Activating transcription factor 6 (ATF6) pathway is the key branch of unfolded protein response (UPR). In this study, a homolog of ATFα from Marsupenaeus japonicus (MjATF6) was identified using genome sequencing and characterized, so as to investigate the role of ATF6 pathway in anti-viral immunity of M. japonicus. The cDNA of MjATF6 obtained was 1008 bp in length, with an open reading frame (ORF) of 849bp, which had encoded a putative of 283 amino acid proteins. Results of qRT-PCR showed that MjATF6 was distributed in all the six tested tissues, with the higher expression level being seen in hemocytes and hepatopancreas...
February 7, 2018: Fish & Shellfish Immunology
Huaqing Cui, Mengsheng Deng, Yonglan Zhang, Fei Yin, Jianhui Liu
Altered proteostasis induced by amyloid peptide aggregation and hyperphosphorylation of tau protein, is a prominent feature of Alzheimer's disease, which highlights the occurrence of endoplasmic reticulum stress and triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis. In this study, we investigated the role of geniposide in the activation of UPR induced by high glucose in primary cortical neurons. We found that high glucose induced a significant activation of UPR, and geniposide enhanced the effect of high glucose on the phosphorylation of IRE1α, the most conserved UPR signaling branch...
February 9, 2018: Neurochemical Research
Thomas Wilhelm, Fabian Bick, Kerstin Peters, Vrinda Mohta, Boaz Tirosh, John B Patterson, Behzad Kharabi-Masouleh, Michael Huber
The intensity and duration of endoplasmic reticulum (ER) stress converts the unfolded protein response (UPR) from an adaptive into a terminal response. The first regulates homeostasis, the latter triggers apoptosis. Cells that rapidly proliferate and possess developed secretory capabilities, such as leukemia cells, depend on an efficiently operating UPR to maintain proteostasis. Activation of terminal UPR by either blockade of adaptive UPR or exaggeration of ER stress has been explored as a novel approach in cancer therapy...
January 9, 2018: Oncotarget
Tian-Ju Ma, Di-Hui Lan, Shou-Zhi He, Zi Ye, Peng Li, Wei Zhai, Wen-Qian Chen, Yang Huang, Yu Fu, Ang Sun, Yi-Bing Wang, Zheng Ye, Jing-Lan Li, Yi Gao, Xin-Lin Yan, Zhao-Hui Li
Our previous study has shown heme oxygenase-1 (HO-1) protects human lens epithelial cells (LECs) against H2O2-induced oxidative stress and apoptosis. Nrf2, the major regulator of HO-1, is triggered during the mutual induction of oxidative stress and ER stress. In response to ER stress, unfolded protein response (UPR) serves as a program of transcriptional and translational regulation mechanism with PERK involved. Both Nrf2 and ATF4 are activated as the downstream effect of PERK signaling coordinating the convergence of dual stresses...
February 2, 2018: Experimental Eye Research
Sonia Ciotti, Riccardo Sgarra, Andrea Sgorbissa, Carlotta Penzo, Andrea Tomasella, Federico Casarsa, Fabio Benedetti, Federico Berti, Guidalberto Manfioletti, Claudio Brancolini
Diaryldienone derivatives with accessible β-carbons show strong anti-neoplastic properties, related to their ability to make covalent adducts with free thiols by Michael addition, and low toxicity in vivo. Accumulation of poly-ubiquitylated proteins, activation of the unfolded protein response (UPR) and induction of cell death are universal hallmarks of their activities. These compounds have been characterized as inhibitors of isopeptidases, a family of cysteine-proteases, which de-conjugate ubiquitin and ubiquitin-like proteins from their targets...
February 7, 2018: Cell Death & Disease
Milan Hano, Lenka Tomášová, Mário Šereš, Lucia Pavlíková, Albert Breier, Zdena Sulová
Multidrug resistance (MDR) is a phenotype of cancer cells with reduced sensitivity to a wide range of unrelated drugs. P-glycoprotein (P-gp)-a drug efflux pump (ABCB1 member of the ABC transporter gene family)-is frequently observed to be a molecular cause of MDR. The drug-efflux activity of P-gp is considered as the underlying mechanism of drug resistance against P-gp substrates and results in failure of cancer chemotherapy. Several pathological impulses such as shortages of oxygen and glucose supply, alterations of calcium storage mechanisms and/or processes of protein N-glycosylation in the endoplasmic reticulum (ER) leads to ER stress (ERS), characterized by elevation of unfolded protein cell content and activation of the unfolded protein response (UPR)...
February 6, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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