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CRISPR/Cas9 cell death

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https://www.readbyqxmd.com/read/28627410/current-and-upcoming-mitochondrial-targets-for-cancer-therapy
#1
REVIEW
Hyoung Kyu Kim, Yeon Hee Noh, Bernd Nilius, Kyung Soo Ko, Byoung Doo Rhee, Nari Kim, Jin Han
Mitochondria are essential intracellular organelles that regulate energy metabolism, cell death, and signaling pathways that are important for cell proliferation and differentiation. Therefore, mitochondria are fundamentally implicated in cancer biology, including initiation, growth, metastasis, relapse, and acquired drug resistance. Based on these implications, mitochondria have been proposed as a major therapeutic target for cancer treatment. In addition to classical view of mitochondria in cancer biology, recent studies found novel pathophysiological roles of mitochondria in cancer...
June 13, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28620317/comparative-and-experimental-studies-on-the-genes-altered-by-chronic-hypoxia-in-human-brain-microendothelial-cells
#2
Eugenia Mata-Greenwood, Dipali Goyal, Ravi Goyal
Background : Hypoxia inducible factor 1 alpha (HIF1A) is a master regulator of acute hypoxia; however, with chronic hypoxia, HIF1A levels return to the normoxic levels. Importantly, the genes that are involved in the cell survival and viability under chronic hypoxia are not known. Therefore, we tested the hypothesis that chronic hypoxia leads to the upregulation of a core group of genes with associated changes in the promoter DNA methylation that mediates the cell survival under hypoxia. Results : We examined the effect of chronic hypoxia (3 days; 0...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28574502/hepatitis-b-virus-x-protein-promotes-creb-mediated-activation-of-mir-3188-and-notch-signaling-in-hepatocellular-carcinoma
#3
Shao-Jun Zhou, Yue-Ling Deng, Hui-Fang Liang, Jonathan C Jaoude, Fu-Yao Liu
Familiar clustering of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) has been frequently reported. However, limited information is available about the underlying molecular mechanisms in HBV-related HCC patients with family history of HCC. In our previous study, Agilent miRNA Base 16.0 microarray showed miRNA profiles of the plasma of HBV-related HCC patients who had a family history of HCC. This study aims to explore the expression, function, and mechanisms of miR-3188 in HCC that might provide novel insights into the role of family history on the risk of HCC...
June 2, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28566761/proof-of-concept-gene-editing-for-the-murine-model-of-inducible-arginase-1-deficiency
#4
Yuan Yan Sin, Phillipe R Price, Laurel L Ballantyne, Colin D Funk
Arginase-1 deficiency in humans is a rare genetic disorder of metabolism resulting from a loss of arginase-1, leading to impaired ureagenesis, hyperargininemia and neurological deficits. Previously, we generated a tamoxifen-inducible arginase-1 deficient mouse model harboring a deletion of Arg1 exons 7 and 8 that leads to similar biochemical defects, along with a wasting phenotype and death within two weeks. Here, we report a strategy utilizing the Clustered, Regularly Interspaced, Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system in conjunction with piggyBac technology to target and reincorporate exons 7 and 8 at the specific Arg1 locus in attempts to restore the function of arginase-1 in induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs) and macrophages in vitro...
May 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28551825/necroptosis-and-ferroptosis-are-alternative-cell-death-pathways-that-operate-in-acute-kidney-failure
#5
Tammo Müller, Christin Dewitz, Jessica Schmitz, Anna Sophia Schröder, Jan Hinrich Bräsen, Brent R Stockwell, James M Murphy, Ulrich Kunzendorf, Stefan Krautwald
Ferroptosis is a recently recognized caspase-independent form of regulated cell death that is characterized by the accumulation of lethal lipid ROS produced through iron-dependent lipid peroxidation. Considering that regulation of fatty acid metabolism is responsible for the membrane-resident pool of oxidizable fatty acids that undergo lipid peroxidation in ferroptotic processes, we examined the contribution of the key fatty acid metabolism enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), in regulating ferroptosis...
May 27, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28549975/knockdown-of-epigenetic-transcriptional-co-regulator-brd2a-disrupts-apoptosis-and-proper-formation-of-hindbrain-and-midbrain-hindbrain-boundary-mhb-region-in-zebrafish
#6
Tami Murphy, Heather Melville, Eliza Fradkin, Giana Bistany, Gregory Branigan, Kelly Olsen, Catharine R Comstock, Hayley Hanby, Ellie Garbade, Angela J DiBenedetto
Brd2 is a member of the bromodomain-extraterminal domain (BET) family of proteins and functions as an acetyl-histone-directed transcriptional co-regulator and recruitment scaffold in chromatin modification complexes affecting signal-dependent transcription. While Brd2 acts as a protooncogene in mammalian blood, developmental studies link it to regulation of neuronal apoptosis and epilepsy, and complete knockout of the gene is invariably embryonic lethal. In Drosophila, the Brd2 homolog acts as a maternal effect factor necessary for segment formation and identity and proper expression of homeotic loci, including Ultrabithorax and engrailed...
May 23, 2017: Mechanisms of Development
https://www.readbyqxmd.com/read/28528977/imatinib-induces-autophagy-via-upregulating-xiap-in-gist882%C3%A2-cells
#7
Qingqing Xie, Qi Lin, Dezhi Li, Jianming Chen
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms originating from the gastrointestinal tract with gain of function mutations in receptor tyrosine kinases KIT or platelet-derived growth factor receptor A (PDGFRA). The main effective treatment for GISTs is tyrosine kinase inhibitors, such as imatinib mesylate. However, GISTs respond to imatinib treatment eventually develop acquired resistance, which is a main obstacle for GISTs therapy. Therefore, it's urgent to have a better understanding of the mechanisms underlying the imatinib resistance in GISTs to develop novel therapeutic strategies...
May 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28514664/lack-of-mttp-activity-in-pluripotent-stem-cell-derived-hepatocytes-and-cardiomyocytes-abolishes-apob-secretion-and-increases-cell-stress
#8
Ying Liu, Donna M Conlon, Xin Bi, Katherine J Slovik, Jianting Shi, Hailey I Edelstein, John S Millar, Ali Javaheri, Marina Cuchel, Evanthia E Pashos, Jahangir Iqbal, M Mahmood Hussain, Robert A Hegele, Wenli Yang, Stephen A Duncan, Daniel J Rader, Edward E Morrisey
Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTP(R46G)), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids...
May 16, 2017: Cell Reports
https://www.readbyqxmd.com/read/28502081/simultaneous-modification-of-three-homoeologs-of-taedr1-by-genome-editing-enhances-powdery-mildew-resistance-in-wheat
#9
Yunwei Zhang, Yang Bai, Guangheng Wu, Shenghao Zou, Yongfang Chen, Caixia Gao, Dingzhong Tang
Wheat (Triticum aestivum L.) incurs significant yield losses from powdery mildew, a major fungal disease caused by Blumeria graminis f. sp. tritici, (Bgt). ENHANCED DISEASE RESISTANCE1 (EDR1) plays a negative role in the defense response against powdery mildew in Arabidopsis thaliana; however, the edr1 mutant does not show constitutively activated defense responses. This makes EDR1 an ideal target for approaches using new genome-editing tools to improve powdery mildew resistance. We cloned TaEDR1 from hexaploid wheat and found high similarity among the three homoeologs of EDR1...
May 14, 2017: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/28494239/crispr-cas9-screens-reveal-epstein-barr-virus-transformed-b-cell-host-dependency-factors
#10
Yijie Ma, Michael J Walsh, Katharina Bernhardt, Camille W Ashbaugh, Stephen J Trudeau, Isabelle Y Ashbaugh, Sizun Jiang, Chang Jiang, Bo Zhao, David E Root, John G Doench, Benjamin E Gewurz
Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma (BL) and immunosuppression-related lymphomas. These B cell malignancies arise by distinct transformation pathways and have divergent viral and host expression programs. To identify host dependency factors resulting from these EBV+, B cell-transformed cell states, we performed parallel genome-wide CRISPR/Cas9 loss-of-function screens in BL and lymphoblastoid cell lines (LCLs). These highlighted 57 BL and 87 LCL genes uniquely important for their growth and survival...
May 10, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28475715/reep6-deficiency-leads-to-retinal-degeneration-through-disruption-of-er-homeostasis-and-protein-trafficking
#11
Smriti A Agrawal, Thomas Burgoyne, Aiden Eblimit, James Bellingham, David A Parfitt, Amelia Lane, Ralph Nichols, Chinwe Asomugha, Matthew J Hayes, Peter M Munro, Mingchu Xu, Keqing Wang, Clare E Futter, Yumei Li, Rui Chen, Michael E Cheetham
Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy. We recently identified mutations in REEP6, which encodes the receptor expression enhancing protein 6, in several families with autosomal recessive RP. REEP6 is related to the REEP and Yop1p family of ER shaping proteins and potential receptor accessory proteins, but the role of REEP6 in the retina is unknown. Here we characterise the disease mechanisms associated with loss of REEP6 function using a Reep6 knockout mouse generated by CRISPR/Cas9 gene editing...
May 5, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28475172/keratins-regulate-colonic-epithelial-cell-differentiation-through-the-notch1-signalling-pathway
#12
Iris A K Lähdeniemi, Julia O Misiorek, Christian J M Antila, Sebastian K-J Landor, Carl-Gustaf A Stenvall, Lina E Fortelius, Linda K Bergström, Cecilia Sahlgren, Diana M Toivola
Keratins (K) are intermediate filament proteins important in stress protection and mechanical support of epithelial tissues. K8, K18 and K19 are the main colonic keratins, and K8-knockout (K8(-/-)) mice display a keratin dose-dependent hyperproliferation of colonic crypts and a colitis-phenotype. However, the impact of the loss of K8 on intestinal cell differentiation has so far been unknown. Here we show that K8 regulates Notch1 signalling activity and differentiation in the epithelium of the large intestine...
June 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28461573/genetic-and-small-molecule-disruption-of-the-aid-rad51-axis-similarly-protects-nonobese-diabetic-mice-from-type-1-diabetes-through-expansion-of-regulatory-b-lymphocytes
#13
Jeremy J Ratiu, Jeremy J Racine, Muneer G Hasham, Qiming Wang, Jane A Branca, Harold D Chapman, Jing Zhu, Nina Donghia, Vivek Philip, William H Schott, Clive Wasserfall, Mark A Atkinson, Kevin D Mills, Caroline M Leeth, David V Serreze
B lymphocytes play a key role in type 1 diabetes (T1D) development by serving as a subset of APCs preferentially supporting the expansion of autoreactive pathogenic T cells. As a result of their pathogenic importance, B lymphocyte-targeted therapies have received considerable interest as potential T1D interventions. Unfortunately, the B lymphocyte-directed T1D interventions tested to date failed to halt β cell demise. IgG autoantibodies marking humans at future risk for T1D indicate that B lymphocytes producing them have undergone the affinity-maturation processes of class switch recombination and, possibly, somatic hypermutation...
June 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28415820/targeting-programmed-cell-death-ligand-1-by-crispr-cas9-in-osteosarcoma-cells
#14
Yunfei Liao, Lulu Chen, Yong Feng, Jacson Shen, Yan Gao, Gregory Cote, Edwin Choy, David Harmon, Henry Mankin, Francis Hornicek, Zhenfeng Duan
Programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is expressed on tumor cells that suppresses the T cell-mediated immune response. Therapies targeting the PD-L1 pathway promote anti-tumor immunity and have shown promising results in some types of cancers. However, the functional and therapeutic roles of PD-L1 in osteosarcoma remain largely unknown. In this study, we found that PD-L1 protein was expressed in osteosarcoma cell lines and tissue microarray of patient tumors. Tissue microarray immunohistochemistry analysis showed that the overall and five-year survival rates of patients with high levels of PD-L1 expression were significantly shorter than patients with low levels...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28389661/crispr-cas9-mediated-pd-1-disruption-enhances-anti-tumor-efficacy-of-human-chimeric-antigen-receptor-t-cells
#15
Levi J Rupp, Kathrin Schumann, Kole T Roybal, Rachel E Gate, Chun J Ye, Wendell A Lim, Alexander Marson
Immunotherapies with chimeric antigen receptor (CAR) T cells and checkpoint inhibitors (including antibodies that antagonize programmed cell death protein 1 [PD-1]) have both opened new avenues for cancer treatment, but the clinical potential of combined disruption of inhibitory checkpoints and CAR T cell therapy remains incompletely explored. Here we show that programmed death ligand 1 (PD-L1) expression on tumor cells can render human CAR T cells (anti-CD19 4-1BBζ) hypo-functional, resulting in impaired tumor clearance in a sub-cutaneous xenograft model...
April 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28386364/nestin-servers-as-a-promising-prognostic-biomarker-in-non-small-cell-lung-cancer
#16
Fang Liu, Yuan Zhang, Ming Lu, Cong Wang, Qingbao Li, Yongsheng Gao, Dianbin Mu, Yan Cao, Miaomiao Li, Xiangjiao Meng
Lung cancer is currently the leading cause of cancer-related death worldwide and it is important to identify the predictive and/or prognostic markers for the cancer. Nestin, a proliferative and multipotent biomarker has been reported to be associated with prognosis in non-small cell lung cancer (NSCLC) in a few studies. In the present study, we retrospectively recruited 153 patients with NSCLC. Nestin protein expression in tumor samples was determined by immunohistochemistry staining. Nestin expression was related with tumor differentiation (P=0...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28384611/bid-links-ferroptosis-to-mitochondrial-cell-death-pathways
#17
Sandra Neitemeier, Anja Jelinek, Vincenzo Laino, Lena Hoffmann, Ina Eisenbach, Roman Eying, Goutham K Ganjam, Amalia M Dolga, Sina Oppermann, Carsten Culmsee
Ferroptosis has been defined as an oxidative and iron-dependent pathway of regulated cell death that is distinct from caspase-dependent apoptosis and established pathways of death receptor-mediated regulated necrosis. While emerging evidence linked features of ferroptosis induced e.g. by erastin-mediated inhibition of the Xc(-) system or inhibition of glutathione peroxidase 4 (Gpx4) to an increasing number of oxidative cell death paradigms in cancer cells, neurons or kidney cells, the biochemical pathways of oxidative cell death remained largely unclear...
August 2017: Redox Biology
https://www.readbyqxmd.com/read/28362255/ribonuclease-l-mediates-the-cell-lethal-phenotype-of-double-stranded-rna-editing-enzyme-adar1-deficiency-in-a-human-cell-line
#18
Yize Li, Shuvojit Banerjee, Stephen A Goldstein, Beihua Dong, Christina Gaughan, Sneha Rath, Jesse Donovan, Alexei Korennykh, Robert H Silverman, Susan R Weiss
ADAR1 isoforms are adenosine deaminases that edit and destabilize double-stranded RNA reducing its immunostimulatory activities. Mutation of ADAR1 leads to a severe neurodevelopmental and inflammatory disease of children, Aicardi-Goutiéres syndrome. In mice, Adar1 mutations are embryonic lethal but are rescued by mutation of the Mda5 or Mavs genes, which function in IFN induction. However, the specific IFN regulated proteins responsible for the pathogenic effects of ADAR1 mutation are unknown. We show that the cell-lethal phenotype of ADAR1 deletion in human lung adenocarcinoma A549 cells is rescued by CRISPR/Cas9 mutagenesis of the RNASEL gene or by expression of the RNase L antagonist, murine coronavirus NS2 accessory protein...
March 31, 2017: ELife
https://www.readbyqxmd.com/read/28356341/essential-role-for-centromeric-factors-following-p53-loss-and-oncogenic-transformation
#19
Dan Filipescu, Monica Naughtin, Katrina Podsypanina, Vincent Lejour, Laurence Wilson, Zachary A Gurard-Levin, Guillermo A Orsi, Iva Simeonova, Eleonore Toufektchan, Laura D Attardi, Franck Toledo, Geneviève Almouzni
In mammals, centromere definition involves the histone variant CENP-A (centromere protein A), deposited by its chaperone, HJURP (Holliday junction recognition protein). Alterations in this process impair chromosome segregation and genome stability, which are also compromised by p53 inactivation in cancer. Here we found that CENP-A and HJURP are transcriptionally up-regulated in p53-null human tumors. Using an established mouse embryonic fibroblast (MEF) model combining p53 inactivation with E1A or HRas-V12 oncogene expression, we reproduced a similar up-regulation of HJURP and CENP-A...
March 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28351990/an-nadph-oxidase-rboh-functions-in-rice-roots-during-lysigenous-aerenchyma-formation-under-oxygen-deficient-conditions
#20
Takaki Yamauchi, Miki Yoshioka, Aya Fukazawa, Hitoshi Mori, Naoko K Nishizawa, Nobuhiro Tsutsumi, Hirofumi Yoshioka, Mikio Nakazono
Reactive oxygen species (ROS) produced by the NADPH oxidase, respiratory burst oxidase homolog (RBOH), trigger signal transduction in diverse biological processes in plants. However, the functions of RBOH homologs in rice (Oryza sativa) and other gramineous plants are poorly understood. Ethylene induces the formation of lysigenous aerenchyma, which consists of internal gas spaces created by programmed cell death of cortical cells, in roots of gramineous plants under oxygen-deficient conditions. Here, we report that, in rice, one RBOH isoform (RBOHH) has a role in ethylene-induced aerenchyma formation in roots...
April 2017: Plant Cell
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