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CRISPR/Cas9 cell death

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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
#1
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
#2
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
#3
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
#4
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
#5
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 immortalised human myoblasts. Though myoblasts expressing PAX3-FOXO1 or MYCN alone were not transformed in focus formation assays, combined PAX3-FOXO1 and MYCN expression resulted in transformation...
January 31, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28137860/creatine-maintains-intestinal-homeostasis-and-protects-against-colitis
#6
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)...
January 30, 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
#7
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
#8
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...
January 20, 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
#9
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 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...
January 15, 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/28073774/temporally-distinct-pd-l1-expression-by-tumor-and-host-cells-contributes-to-immune-escape
#10
Takuro Noguchi, Jeffrey P Ward, Matthew M Gubin, Cora D Arthur, Sang Hun Lee, Jasreet Hundal, Mark J Selby, Robert F Graziano, Elaine R Mardis, Alan J Korman, Robert D Schreiber
Antibody blockade of programmed death-1 (PD-1) or its ligand, PD-L1, has led to unprecedented therapeutic responses in certain tumor-bearing individuals, but PD-L1 expression's prognostic value in stratifying cancer patients for such treatment remains unclear. Reports conflict on the significance of correlations between PD-L1 on tumor cells and positive clinical outcomes to PD-1/PD-L1 blockade. We investigated this issue using genomically related, clonal subsets from the same methylcholanthrene-induced sarcoma: a highly immunogenic subset that is spontaneously eliminated in vivo by adaptive immunity and a less immunogenic subset that forms tumors in immunocompetent mice, but is sensitive to PD-1/PD-L1 blockade therapy...
February 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28060411/scarless-cas9-assisted-recombineering-no-scar-in-escherichia-coli-an-easy-to-use-system-for-genome-editing
#11
Christopher R Reisch, Kristala L J Prather
The discovery and development of genome editing systems that leverage the site-specific DNA endonuclease system CRISPR/Cas9 has fundamentally changed the ease and speed of genome editing in many organisms. In eukaryotes, the CRISPR/Cas9 system utilizes a "guide" RNA to enable the Cas9 nuclease to make a double-strand break at a particular genome locus, which is repaired by non-homologous end joining (NHEJ) repair enzymes, often generating random mutations in the process. A specific alteration of the target genome can also be generated by supplying a DNA template in vivo with a desired mutation, which is incorporated by homology-directed repair...
January 5, 2017: Current Protocols in Molecular Biology
https://www.readbyqxmd.com/read/28049346/genoproteomics-assisted-improvement-of-andrographis-paniculata-toward-a-promising-molecular-and-conventional-breeding-platform-for-autogamous-plants-affecting-the-pharmaceutical-industry
#12
Alireza Valdiani, Daryush Talei, Surrinder K Lattoo, Rodomiro Ortiz, Søren Kjærsgaard Rasmussen, Jacqueline Batley, Mohd Yusop Rafii, Mahmood Maziah, Kallevettankuzhy K Sabu, Rambod Abiri, Suchirat Sakuanrungsirikul, Soon Guan Tan
Andrographis paniculata (Burm. f.) Wall. ex Nees. (AP) is a hermaphroditic, self-compatible, and habitual inbreeding plant. Its main bioactive component is andrographolide, which is capable of inducing autophagic cell death in some human cancer cells and helps fight HIV/AIDS. Increasing the andrographolide content by investigating the genetic mechanisms controlling its biosynthesis in order to improve and develop high-yielding cultivars are the main breeding targets for AP. However, there might exist some limitations or barriers for crossability within AP accessions...
January 3, 2017: Critical Reviews in Biotechnology
https://www.readbyqxmd.com/read/28024081/deletion-of-the-gaa-repeats-from-the-human-frataxin-gene-using-the-crispr-cas9-system-in-yg8r-derived-cells-and-mouse-models-of-friedreich-ataxia
#13
D L Ouellet, K Cherif, J Rousseau, J P Tremblay
The Friedreich ataxia is a monogenic disease due to a hyperexpanded GAA triplet located within the first intron of the frataxin gene that causes transcriptional issues. The resulting frataxin protein deficiency leads to a Fe-S cluster biosynthesis dysfunction in the mitochondria and to oxidative stress and cell death. Here we use the CRISPR-Cas9 system to remove the mutated GAA expansion and restore the frataxin gene transcriptional activity and protein level. Both YG8R and YG8sR mouse models and cell lines derived from these mice were used to CRISPR-edited successfully the GAA expansion in vitro and in vivo...
January 19, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28007784/an-ensemble-of-regulatory-elements-controls-runx3-spatiotemporal-expression-in-subsets-of-dorsal-root-ganglia-proprioceptive-neurons
#14
Elena Appel, Sarit Weissmann, Yehuda Salzberg, Kira Orlovsky, Varda Negreanu, Michael Tsoory, Calanit Raanan, Ester Feldmesser, Yael Bernstein, Orit Wolstein, Ditsa Levanon, Yoram Groner
The Runx3 transcription factor is essential for development and diversification of the dorsal root ganglia (DRGs) TrkC sensory neurons. In Runx3-deficient mice, developing TrkC neurons fail to extend central and peripheral afferents, leading to cell death and disruption of the stretch reflex circuit, resulting in severe limb ataxia. Despite its central role, the mechanisms underlying the spatiotemporal expression specificities of Runx3 in TrkC neurons were largely unknown. Here we first defined the genomic transcription unit encompassing regulatory elements (REs) that mediate the tissue-specific expression of Runx3...
December 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27978828/integrin-fak-signaling-rapidly-and-potently-promotes-mitochondrial-function-through-stat3
#15
Nishant P Visavadiya, Matthew P Keasey, Vladislav Razskazovskiy, Kalpita Banerjee, Cuihong Jia, Chiharu Lovins, Gary L Wright, Theo Hagg
BACKGROUND: STAT3 is increasingly becoming known for its non-transcriptional regulation of mitochondrial bioenergetic function upon activation of its S727 residue (S727-STAT3). Lengthy mitochondrial dysfunction can lead to cell death. We tested whether an integrin-FAK-STAT3 signaling pathway we recently discovered regulates mitochondrial function and cell survival, and treatments thereof. METHODS: Cultured mouse brain bEnd5 endothelial cells were treated with integrin, FAK or STAT3 inhibitors, FAK siRNA, as well as integrin and STAT3 activators...
15, 2016: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/27966608/slit-robo-gtpase-activating-protein-2-as-a-metastasis-suppressor-in-osteosarcoma
#16
Tracy A Marko, Ghaidan A Shamsan, Elizabeth N Edwards, Paige E Hazelton, Susan K Rathe, Ingrid Cornax, Paula R Overn, Jyotika Varshney, Brandon J Diessner, Branden S Moriarity, M Gerard O'Sullivan, David J Odde, David A Largaespada
Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase-Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 nuclease system and conditional overexpression in the murine osteosarcoma cell lines K12 and K7M2...
December 14, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27902973/cd147-regulates-extrinsic-apoptosis-in-spermatocytes-by-modulating-nf%C3%AE%C2%BAb-signaling-pathways
#17
Chaoqun Wang, Kin Lam Fok, Zhiming Cai, Hao Chen, Hsiao Chang Chan
CD147 null mutant male mice are infertile with arrested spermatogenesis and increased apoptotic germ cells. Our previous studies have shown that CD147 prevents apoptosis in mouse spermatocytes but not spermatogonia. However, the underlying mechanism remains elusive. In the present study, we aim to determine the CD147-regulated apoptotic pathway in mouse spermatocytes. Our results showed that immunodepletion of CD147 triggered apoptosis through extrinsic apoptotic pathway in mouse testis and spermatocyte cell line (GC-2 cells), accompanied by activation of non-canonical NFκB signaling and suppression of canonical NFκB signaling...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/27898091/restoring-ureagenesis-in-hepatocytes-by-crispr-cas9-mediated-genomic-addition-to-arginase-deficient-induced-pluripotent-stem-cells
#18
Patrick C Lee, Brian Truong, Agustin Vega-Crespo, W Blake Gilmore, Kip Hermann, Stephanie Ak Angarita, Jonathan K Tang, Katherine M Chang, Austin E Wininger, Alex K Lam, Benjamen E Schoenberg, Stephen D Cederbaum, April D Pyle, James A Byrne, Gerald S Lipshutz
Urea cycle disorders are incurable enzymopathies that affect nitrogen metabolism and typically lead to hyperammonemia. Arginase deficiency results from a mutation in Arg1, the enzyme regulating the final step of ureagenesis and typically results in developmental disabilities, seizures, spastic diplegia, and sometimes death. Current medical treatments for urea cycle disorders are only marginally effective, and for proximal disorders, liver transplantation is effective but limited by graft availability. Advances in human induced pluripotent stem cell research has allowed for the genetic modification of stem cells for potential cellular replacement therapies...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27780859/the-second-generation-exportin-1-inhibitor-kpt-8602-demonstrates-potent-activity-against-acute-lymphoblastic-leukemia
#19
Thomas Vercruysse, Jolien De Bie, Jasper Neggers, Maarten Jacquemyn, Els Vanstreels, Jonathan Leo Schmid-Burgk, Veit Hornung, Erkan Baloglu, Yosef Landesman, William Senapedis, Sharon Shacham, Antonis Dagklis, Jan Cools, Dirk Daelemans
PURPOSE: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports many cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibition of XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in Phase-II/IIb clinical trials when dosed 1 - 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily...
October 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27780223/lim-only-protein-4-lmo4-and-lim-domain-binding-protein-1-ldb1-promote-growth-and-metastasis-of-human-head-and-neck-cancer-lmo4-and-ldb1-in-head-and-neck-cancer
#20
Elizabeth A Simonik, Ying Cai, Katherine N Kimmelshue, Dana M Brantley-Sieders, Holli A Loomans, Claudia D Andl, Grant M Westlake, Victoria M Youngblood, Jin Chen, Wendell G Yarbrough, Brandee T Brown, Lalitha Nagarajan, Stephen J Brandt
Squamous cell carcinoma of the head and neck (HNSCC) accounts for more than 300,000 deaths worldwide per year as a consequence of tumor cell invasion of adjacent structures or metastasis. LIM-only protein 4 (LMO4) and LIM-domain binding protein 1 (LDB1), two directly interacting transcriptional adaptors that have important roles in normal epithelial cell differentiation, have been associated with increased metastasis, decreased differentiation, and shortened survival in carcinoma of the breast. Here, we implicate two LDB1-binding proteins, single-stranded binding protein 2 (SSBP2) and 3 (SSBP3), in controlling LMO4 and LDB1 protein abundance in HNSCC and in regulating specific tumor cell functions in this disease...
2016: PloS One
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