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CRISPR/Cas9 cell death

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https://www.readbyqxmd.com/read/28415820/targeting-programmed-cell-death-ligand-1-by-crispr-cas9-in-osteosarcoma-cells
#1
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...
March 17, 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
#2
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
#3
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
#4
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...
March 9, 2017: Redox Biology
https://www.readbyqxmd.com/read/28362255/ribonuclease-l-mediates-the-cell-lethal-phenotype-of-the-double-stranded-rna-editing-enzyme-adar1-in-a-human-cell-line
#5
Yize Li, Shuvojit Banerjee, Stephen A Goldstein, Beihua Dong, Christina Gaughan, Sneha Rath, Jesse Donovan, Alexei V 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
#6
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 29, 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
#7
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 homologues 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...
March 28, 2017: Plant Cell
https://www.readbyqxmd.com/read/28294316/knockout-of-atg5-leads-to-malignant-cell-transformation-and-resistance-to-src-family-kinase-inhibitor-pp2
#8
Sung-Hee Hwang, Byeal-I Han, Michael Lee
Autophagy can either promote or inhibit cell death in different cellular contexts. In this study, we investigated the role of autophagy in ATG5 knockout (KO) cell line established using CRISPR/Cas9 system. In ATG5 KO cells, RT-PCR and immunoblot of LC3 confirmed the functional gene knockout. We found that knockout of ATG5 significantly increased proliferation of NIH 3T3 cells. In particular, autophagy deficiency enhanced susceptibility to cellular transformation as determined by an in vitro clonogenic survival assay and a soft agar colony formation assay...
March 15, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28258182/annealing-of-complementary-dna-sequences-during-double-strand-break-repair-in-drosophila-is-mediated-by-the-ortholog-of-smarcal1
#9
Julie Korda Holsclaw, Jeff Sekelsky
DNA double-strand breaks (DSBs) pose a serious threat to genomic integrity. If unrepaired, they can lead to chromosome fragmentation and cell death. If repaired incorrectly, they can cause mutations and chromosome rearrangements. DSBs are repaired using end-joining or homology-directed repair strategies, with the predominant form of homology-directed repair being synthesis-dependent strand annealing (SDSA). SDSA is the first defense against genomic rearrangements and information loss during DSB repair, making it a vital component of cell health and an attractive target for chemotherapeutic development...
March 3, 2017: Genetics
https://www.readbyqxmd.com/read/28248921/development-of-improved-vaccine-cell-lines-against-rotavirus
#10
Weilin Wu, Nichole Orr-Burks, Jon Karpilow, Ralph A Tripp
Rotavirus is a major cause of severe gastroenteritis among very young children. In developing countries, rotavirus is the major cause of mortality in children under five years old, causing up to 20% of all childhood deaths in countries with high diarrheal disease burden, with more than 90% of these deaths occurring in Africa and Asia. Rotavirus vaccination mimics the first infection without causing illness, thus inducing strong and broad heterotypic immunity against prospective rotavirus infections. Two live vaccines are available, Rotarix and RotaTeq, but vaccination efforts are hampered by high production costs...
March 1, 2017: Scientific Data
https://www.readbyqxmd.com/read/28242812/crispr-knockout-of-the-hur-gene-causes-a-xenograft-lethal-phenotype
#11
Shruti Lal, Edwin C Cheung, Mahsa Zarei, Ranjan Preet, Saswati N Chand, Nicole C Mambelli-Lisboa, Carmella Romeo, Matthew C Stout, Eric Londin, Austin Goetz, Cinthya Y Lowder, Avinoam Nevler, Charles J Yeo, Paul M Campbell, Jordan M Winter, Dan A Dixon, Jonathan R Brody
Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer related deaths in the U.S., while colorectal cancer (CRC) is the third most common cancer. The RNA binding protein HuR (ELAVL1), supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and CRC tumor cohorts as compared to normal pancreas and colon tissues, respectively. CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA (MIA PaCa-2 and Hs 766T) and CRC (HCT116) cell lines...
February 27, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28212528/the-crispr-cas9%C3%A2-system-efficiently-reverts-the-tumorigenic-ability-of-bcr-abl-in-vitro-and-in-a-xenograft-model-of-chronic-myeloid-leukemia
#12
Ignacio García-Tuñón, María Hernández-Sánchez, José Luis Ordoñez, Veronica Alonso-Pérez, Miguel Álamo-Quijada, Rocio Benito, Carmen Guerrero, Jesús María Hernández-Rivas, Manuel Sánchez-Martín
CRISPR/Cas9 technology was used to abrogate p210 oncoprotein expression in the Boff-p210 cell line, a pro-B line derived from interlukin-3-dependent Baf/3, that shows IL-3-independence arising from the constitutive expression of BCR-ABL p210. Using this approach, pools of Boff-p210-edited cells and single edited cell-derived clones were obtained and functionally studied in vitro. The loss of p210 expression in Boff-p210 cells resulted in the loss of ability to grow in the absence of IL-3, as the Baf/3 parental line, showing significantly increased apoptosis levels...
February 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28192788/metabolic-gatekeeper-function-of-b-lymphoid-transcription-factors
#13
Lai N Chan, Zhengshan Chen, Daniel Braas, Jae-Woong Lee, Gang Xiao, Huimin Geng, Kadriye Nehir Cosgun, Christian Hurtz, Seyedmehdi Shojaee, Valeria Cazzaniga, Hilde Schjerven, Thomas Ernst, Andreas Hochhaus, Steven M Kornblau, Marina Konopleva, Miles A Pufall, Giovanni Cazzaniga, Grace J Liu, Thomas A Milne, H Phillip Koeffler, Theodora S Ross, Isidro Sánchez-García, Arndt Borkhardt, Keith R Yamamoto, Ross A Dickins, Thomas G Graeber, Markus Müschen
B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply...
February 13, 2017: Nature
https://www.readbyqxmd.com/read/28168724/identification-of-fibulin-1-as-a-human-bone-marrow-stromal-hs-5-cell-derived-factor-that-induces-human-prostate-cancer-cell-death
#14
Kornkamon Lertsuwan, Leila H Choe, Irene R Marwa, Kelvin Lee, Robert A Sikes
BACKGROUND: Previous studies showed that human bone marrow stromal HS-5 cells secreted unidentified factor(s) inducing PCa cell death. Herein, the HS-5-derived factor (HS-5 DF) was characterized and identified. METHODS: Conditioned media from confluent HS-5 cells were collected and modified for biochemical characteristic testing of HS-5 DF. Cell survival was measured by apoptosis assay and live/dead assay. Fibulin-1 was identified from gel electrophoresis and mass spectrometry...
February 7, 2017: Prostate
https://www.readbyqxmd.com/read/28153089/genome-editing-reveals-glioblastoma-addiction-to-microrna-10b
#15
Rachid El Fatimy, Shruthi Subramanian, Erik J Uhlmann, Anna M Krichevsky
Glioblastoma (GBM) brain tumor remains among the most lethal and incurable human diseases. Oncogenic microRNA-10b (miR-10b) is strongly and universally upregulated in GBM, and its inhibition by antisense oligonucleotides (ASOs) reduces the growth of heterogeneous glioma cells; therefore, miR-10b represents a unique therapeutic target for GBM. Here we explored the effects of miR-10b gene editing on GBM. Using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system, we investigated effects of miR-10b gene editing on the growth of cultured human glioma cells, tumor-initiating stem-like cells, and mouse GBM xenografts, as well as the oncogene-induced transformation of normal astrocytes...
February 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28138962/pax3-foxo1-is-essential-for-tumour-initiation-and-maintenance-but-not-recurrence-in-a-human-myoblast-model-of-rhabdomyosarcoma
#16
Puspa R Pandey, Bishwanath Chatterjee, Mary E Olanich, Javed Khan, Markku M Miettinen, Stephen M Hewitt, Frederic G Barr
The PAX3-FOXO1 fusion gene is generated by a 2;13 chromosomal translocation and is a characteristic feature of an aggressive subset of rhabdomyosarcoma (RMS). To dissect the mechanism of oncogene action during RMS tumourigenesis and progression, doxycycline-inducible PAX3-FOXO1 and constitutive MYCN expression constructs were introduced into immortalized human myoblasts. Although myoblasts expressing PAX3-FOXO1 or MYCN alone were not transformed in focus formation assays, combined PAX3-FOXO1 and MYCN expression resulted in transformation...
April 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28137860/creatine-maintains-intestinal-homeostasis-and-protects-against-colitis
#17
Emre Turer, William McAlpine, Kuan-Wen Wang, Tianshi Lu, Xiaohong Li, Miao Tang, Xiaoming Zhan, Tao Wang, Xiaowei Zhan, Chun-Hui Bu, Anne R Murray, Bruce Beutler
Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea-mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS)...
February 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28124028/optimized-crispr-cas9-genome-editing-for-leishmania-and-its-use-to-target-a-multigene-family-induce-chromosomal-translocation-and-study-dna-break-repair-mechanisms
#18
Wen-Wei Zhang, Patrick Lypaczewski, Greg Matlashewski
CRISPR-Cas9-mediated genome editing has recently been adapted for Leishmania spp. parasites, the causative agents of human leishmaniasis. We have optimized this genome-editing tool by selecting for cells with CRISPR-Cas9 activity through cotargeting the miltefosine transporter gene; mutation of this gene leads to miltefosine resistance. This cotargeting strategy integrated into a triple guide RNA (gRNA) expression vector was used to delete all 11 copies of the A2 multigene family; this was not previously possible with the traditional gene-targeting method...
January 2017: MSphere
https://www.readbyqxmd.com/read/28106882/combination-of-iap-antagonist-and-ifn%C3%AE-activates-novel-caspase-10-and-ripk1-dependent-cell-death-pathways
#19
Maria C Tanzer, Nufail Khan, James A Rickard, Nima Etemadi, Najoua Lalaoui, Sukhdeep Kaur Spall, Joanne M Hildebrand, David Segal, Maria Miasari, Diep Chau, WendyWei-Lynn Wong, Mark McKinlay, Srinivas K Chunduru, Christopher A Benetatos, Stephen M Condon, James E Vince, Marco J Herold, John Silke
Peptido-mimetic inhibitor of apoptosis protein (IAP) antagonists (Smac mimetics (SMs)) can kill tumour cells by depleting endogenous IAPs and thereby inducing tumour necrosis factor (TNF) production. We found that interferon-γ (IFNγ) synergises with SMs to kill cancer cells independently of TNF- and other cell death receptor signalling pathways. Surprisingly, CRISPR/Cas9 HT29 cells doubly deficient for caspase-8 and the necroptotic pathway mediators RIPK3 or MLKL were still sensitive to IFNγ/SM-induced killing...
March 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28088877/the-concerted-action-of-type-2-and-type-3-deiodinases-regulates-the-cell-cycle-and-survival-of-basal-cell-carcinoma-cells
#20
Caterina Miro, Raffaele Ambrosio, Maria Angela De Stefano, Daniela Di Girolamo, Emery Di Cicco, Annunziata Gaetana Cicatiello, Giuseppina Mancino, Tommaso Porcelli, Maddalena Raia, Luigi Del Vecchio, Domenico Salvatore, Monica Dentice
BACKGROUND: Thyroid hormones (THs) mediate pleiotropic cellular processes involved in metabolism, cellular proliferation, and differentiation. The intracellular hormonal environment can be tailored by the type 1 and 2 deiodinase enzymes D2 and D3, which catalyze TH activation and inactivation respectively. In many cellular systems, THs exert well-documented stimulatory or inhibitory effects on cell proliferation; however, the molecular mechanisms by which they control rates of cell cycle progression have not yet been entirely clarified...
April 2017: Thyroid: Official Journal of the American Thyroid Association
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