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CRISPR/Cas9 cell death

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https://www.readbyqxmd.com/read/29042501/plasmodium-falciparum-calcium-dependent-protein-kinase-2-is-critical-for-male-gametocyte-exflagellation-but-not-essential-for-asexual-proliferation
#1
Abhisheka Bansal, Alvaro Molina-Cruz, Joseph Brzostowski, Jianbing Mu, Louis H Miller
Drug development efforts have focused mostly on the asexual blood stages of the malaria parasite Plasmodium falciparum Except for primaquine, which has its own limitations, there are no available drugs that target the transmission of the parasite to mosquitoes. Therefore, there is a need to validate new parasite proteins that can be targeted for blocking transmission. P. falciparum calcium-dependent protein kinases (PfCDPKs) play critical roles at various stages of the parasite life cycle and, importantly, are absent in the human host...
October 17, 2017: MBio
https://www.readbyqxmd.com/read/29036432/copb2-is-essential-for-embryogenesis-and-hypomorphic-mutations-cause-human-microcephaly
#2
Andrew DiStasio, Ashley Driver, Kristen Sund, Milene Donlin, Ranjith M Muraleedharan, Shabnam Pooya, Beth Kline-Fath, Kenneth M Kaufman, Cynthia A Prows, Elizabeth Schorry, Biplab DasGupta, Rolf W Stottmann
Primary microcephaly is a congenital brain malformation characterized by a head circumference less than three standard deviations below the mean for age and sex and results in moderate to severe mental deficiencies and decreased lifespan. We recently studied two children with primary microcephaly in an otherwise unaffected family. Exome sequencing identified an autosomal recessive mutation leading to an amino acid substitution in a WD40 domain of the highly conserved Coatomer Protein Complex, Subunit Beta 2 (COPB2)...
September 19, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29024560/enhanced-stem-cell-differentiation-and-immunopurification-of-genome-engineered-human-retinal-ganglion-cells
#3
Valentin M Sluch, Xitiz Chamling, Melissa M Liu, Cynthia A Berlinicke, Jie Cheng, Katherine L Mitchell, Derek S Welsbie, Donald J Zack
Human pluripotent stem cells have the potential to promote biological studies and accelerate drug discovery efforts by making possible direct experimentation on a variety of human cell types of interest. However, stem cell cultures are generally heterogeneous and efficient differentiation and purification protocols are often lacking. Here, we describe the generation of clustered regularly-interspaced short palindromic repeats(CRISPR)-Cas9 engineered reporter knock-in embryonic stem cell lines in which tdTomato and a unique cell-surface protein, THY1...
October 10, 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28976960/cancer-drug-addiction-is-relayed-by-an-erk2-dependent-phenotype-switch
#4
Xiangjun Kong, Thomas Kuilman, Aida Shahrabi, Julia Boshuizen, Kristel Kemper, Ji-Ying Song, Hans W M Niessen, Elisa A Rozeman, Marnix H Geukes Foppen, Christian U Blank, Daniel S Peeper
Observations from cultured cells, animal models and patients raise the possibility that the dependency of tumours on the therapeutic drugs to which they have acquired resistance represents a vulnerability with potential applications in cancer treatment. However, for this drug addiction trait to become of clinical interest, we must first define the mechanism that underlies it. We performed an unbiased CRISPR-Cas9 knockout screen on melanoma cells that were both resistant and addicted to inhibition of the serine/threonine-protein kinase BRAF, in order to functionally mine their genome for 'addiction genes'...
October 12, 2017: Nature
https://www.readbyqxmd.com/read/28945328/inactivated-sendai-virus-particles-upregulate-cancer-cell-icam-1-expression-with-enhancing-nk-cell-sensitivity-on-cancer-cell
#5
Simin Li, Tomoyuki Nishikawa, Yasufumi Kaneda
We have already reported that the inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) envelope (HVJ-E) has multiple anti-cancer effects, including induction of cancer-selective cell death and activation of anti-cancer immunity. HVJ-E stimulates dendritic cells (DCs) to produce cytokines and chemokines such as IFN-β, IL-6, CCL5 and CXCL10, which activate both CD8(+) T cells and NK cells and recruit them to the tumor microenvironment. However, the effect of HVJ-E on modulating the sensitivity of cancer cells to immune cell attack has yet to be investigated...
September 25, 2017: Cancer Science
https://www.readbyqxmd.com/read/28942966/haploinsufficiency-of-the-chromatin-remodeler-bptf-causes-syndromic-developmental-and-speech-delay-postnatal-microcephaly-and-dysmorphic-features
#6
Paweł Stankiewicz, Tahir N Khan, Przemyslaw Szafranski, Leah Slattery, Haley Streff, Francesco Vetrini, Jonathan A Bernstein, Chester W Brown, Jill A Rosenfeld, Surya Rednam, Sarah Scollon, Katie L Bergstrom, Donald W Parsons, Sharon E Plon, Marta W Vieira, Caio R D C Quaio, Wagner A R Baratela, Johanna C Acosta Guio, Ruth Armstrong, Sarju G Mehta, Patrick Rump, Rolph Pfundt, Raymond Lewandowski, Erica M Fernandes, Deepali N Shinde, Sha Tang, Juliane Hoyer, Christiane Zweier, André Reis, Carlos A Bacino, Rui Xiao, Amy M Breman, Janice L Smith, Nicholas Katsanis, Bret Bostwick, Bernt Popp, Erica E Davis, Yaping Yang
Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28939663/hepatoma-intrinsic-ccrk-inhibition-diminishes-myeloid-derived-suppressor-cell-immunosuppression-and-enhances-immune-checkpoint-blockade-efficacy
#7
Jingying Zhou, Man Liu, Hanyong Sun, Yu Feng, Liangliang Xu, Anthony W H Chan, Joanna H Tong, John Wong, Charing Ching Ning Chong, Paul B S Lai, Hector Kwong-Sang Wang, Shun-Wa Tsang, Tyler Goodwin, Rihe Liu, Leaf Huang, Zhiwei Chen, Joseph Jy Sung, King Lau Chow, Ka Fai To, Alfred Sze-Lok Cheng
OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC). DESIGN: Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems...
September 22, 2017: Gut
https://www.readbyqxmd.com/read/28937686/serine-392-phosphorylation-modulates-p53-mitochondrial-translocation-and-transcription-independent-apoptosis
#8
Cédric Castrogiovanni, Béranger Waterschoot, Olivier De Backer, Patrick Dumont
The tumor suppressor p53 is a key regulator of apoptosis induced by various cellular stresses. p53 can induce apoptosis by two mechanisms. First, p53 acts as a transcription factor inducing and repressing pro-apoptotic and anti-apoptotic targets genes, respectively. Second, p53 is able to translocate to the mitochondria, where it interacts with BCL-2 family members to induce membrane permeabilization and cytochrome c release. p53 transcriptional activity is regulated by a set of post-translational modifications that have been well documented...
September 22, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28935250/engineered-cells-for-costimulatory-enhancement-combined-with-il-21-enhance-the-generation-of-pd-1-disrupted-ctls-for-adoptive-immunotherapy
#9
Jie Shao, Qiuping Xu, Shu Su, Fanyan Meng, Zhengyun Zou, Fangjun Chen, Juan Du, Xiaoping Qian, Baorui Liu
Blockade of the immune cell checkpoint inhibitors programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) has become a powerful tool in cancer treatment, which is effective across various solid cancer types and hematologic malignancies. Our previous studies showed that by reducing immune tolerance, clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) modified cytotoxic T lymphocytes (CTLs) rank highly in terms of immune responses and cytotoxicity. In this study, a genetically modified K562 cell line with surface expression of 4-1BBL was developed to expand PD-1-disrupted CTLs in vitro for further adoptive immunotherapy against cancer...
September 7, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28915012/managing-the-sos-response-for-enhanced-crispr-cas-based-recombineering-in-e-%C3%A2-coli-through-transient-inhibition-of-host-reca-activity
#10
Eirik Adim Moreb, Benjamin Hoover, Adam Yaseen, Nisakorn Valyasevi, Zoe Roecker, Romel Menacho-Melgar, Michael D Lynch
Phage-derived "recombineering" methods are utilized for bacterial genome editing. Recombineering results in a heterogeneous population of modified and unmodified chromosomes, and therefore selection methods, such as CRISPR-Cas9, are required to select for edited clones. Cells can evade CRISPR-Cas-induced cell death through recA-mediated induction of the SOS response. The SOS response increases RecA dependent repair as well as mutation rates through induction of the umuDC error prone polymerase. As a result, CRISPR-Cas selection is more efficient in recA mutants...
October 2, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28888577/crispr-knock-out-ctla-4-enhances-the-anti-tumor-activity-of-cytotoxic-t-lymphocytes
#11
Long Shi, Tongyu Meng, Zhilong Zhao, Jinsheng Han, Wei Zhang, Fei Gao, Jianhui Cai
T cell-mediated anti-tumor immunity plays a pivotal role in cancer immune surveillance. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a protein receptor mainly expressed in activated T cells and regulatory T cells. CTLA-4 competes with CD28 for ligand binding and generates inhibitory signals to attenuate T cell activation. The blockade of CTLA-4 mediated immune inhibitory checkpoint has been associated with enhanced anti-tumor immunity. In this study, we use CRISPR-Cas9 system to knock out (KO) CTLA-4 from cytotoxic T lymphocytes (CTLs) and evaluate its effect on the anti-tumor activity of the CTLs...
December 15, 2017: Gene
https://www.readbyqxmd.com/read/28868328/creating-a-raw264-7-crispr-cas9-genome-wide-library
#12
Brooke A Napier, Denise M Monack
The bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome editing tools are used in mammalian cells to knock-out specific genes of interest to elucidate gene function. The CRISPR-Cas9 system requires that the mammalian cell expresses Cas9 endonuclease, guide RNA (gRNA) to lead the endonuclease to the gene of interest, and the PAM sequence that links the Cas9 to the gRNA. CRISPR-Cas9 genome wide libraries are used to screen the effect of each gene in the genome on the cellular phenotype of interest, in an unbiased high-throughput manner...
May 20, 2017: Bio-protocol
https://www.readbyqxmd.com/read/28864268/baicalein-induces-cell-death-in-murine-t-cell-lymphoma-via-inhibition-of-thioredoxin-system
#13
Raghavendra S Patwardhan, Debojyoti Pal, Rahul Checker, Deepak Sharma, Santosh K Sandur
We have earlier demonstrated the radioprotective potential of baicalein using murine splenic lymphocytes. Here, we have studied the effect of baicalein on murine T cell lymphoma EL4 cells and investigated the underlying mechanism of action. We observed that baicalein induced a dose dependent cell death in EL4 cells in vitro and significantly reduced the frequency of cancer stem cells. Previously, we have reported that murine and human T cell lymphoma cells have increased oxidative stress tolerance capacity due to active thioredoxin system...
October 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28827413/differential-regulation-of-pro-inflammatory-cytokine-signalling-by-ptps-in-pancreatic-%C3%AE-cells
#14
William J Stanley, Prerak M Trivedi, Andrew P Sutherland, Helen Thomas, Esteban N Gurzov
Type 1 diabetes (T1D) is characterized by the destruction of insulin-producing β-cells by immune cells in the pancreas. Pro-inflammatory including TNF-α, IFN-γ and IL-1β are released in the islet during the autoimmune assault and signal in β-cells through phosphorylation cascades, resulting in pro-apoptotic gene expression and eventually β-cell death. Protein tyrosine phosphatases (PTPs) are a family of enzymes that regulate phosphorylative signalling, and are associated with the development of T1D. Here, we observed expression of PTPN6 and PTPN1 in human islets and islets from non-obese diabetic (NOD) mice...
August 21, 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/28813417/cmtm6-maintains-the-expression-of-pd-l1-and-regulates-anti-tumour-immunity
#15
Marian L Burr, Christina E Sparbier, Yih-Chih Chan, James C Williamson, Katherine Woods, Paul A Beavis, Enid Y N Lam, Melissa A Henderson, Charles C Bell, Sabine Stolzenburg, Omer Gilan, Stuart Bloor, Tahereh Noori, David W Morgens, Michael C Bassik, Paul J Neeson, Andreas Behren, Phillip K Darcy, Sarah-Jane Dawson, Ilia Voskoboinik, Joseph A Trapani, Jonathan Cebon, Paul J Lehner, Mark A Dawson
Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) to subvert T-cell-mediated immunosurveillance. The success of therapies that disrupt PD-L1-mediated tumour tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression. Here we identify the uncharacterized protein CMTM6 as a critical regulator of PD-L1 in a broad range of cancer cells, by using a genome-wide CRISPR-Cas9 screen. CMTM6 is a ubiquitously expressed protein that binds PD-L1 and maintains its cell surface expression...
September 7, 2017: Nature
https://www.readbyqxmd.com/read/28768188/blockage-of-core-fucosylation-reduces-cell-surface-expression-of-pd-1-and-promotes-anti-tumor-immune-responses-of-t-cells
#16
Masahiro Okada, Shunsuke Chikuma, Taisuke Kondo, Sana Hibino, Hiroaki Machiyama, Tadashi Yokosuka, Miyako Nakano, Akihiko Yoshimura
Programmed cell death 1 (PD-1) is highly expressed on exhausted T cells and inhibits T cell activation. Antibodies that block the interaction between PD-1 and its ligand prevent this inhibitory signal and reverse T cell dysfunction, providing beneficial anti-tumor responses in a substantial number of patients. Mechanisms for the induction and maintenance of high PD-1 expression on exhausted T cells have not been fully understood. Utilizing a genome-wide loss-of-function screening method based on the CRISPR-Cas9 system, we identified genes involved in the core fucosylation pathway as positive regulators of cell-surface PD-1 expression...
August 1, 2017: Cell Reports
https://www.readbyqxmd.com/read/28767691/crispr-cas9-mediated-knockout-of-c-rel-in-hela-cells-results-in-profound-defects-of-the-cell-cycle
#17
Carsten Slotta, Thomas Schlüter, Lucia M Ruiz-Perera, Hussamadin M Kadhim, Tobias Tertel, Elena Henkel, Wolfgang Hübner, Johannes F W Greiner, Thomas Huser, Barbara Kaltschmidt, Christian Kaltschmidt
Cervical cancer is the fourth common cancer in women resulting worldwide in 266,000 deaths per year. Belonging to the carcinomas, new insights into cervical cancer biology may also have great implications for finding new treatment strategies for other kinds of epithelial cancers. Although the transcription factor NF-κB is known as a key player in tumor formation, the relevance of its particular subunits is still underestimated. Here, we applied CRISPR/Cas9n-mediated genome editing to successfully knockout the NF-κB subunit c-REL in HeLa Kyoto cells as a model system for cervical cancers...
2017: PloS One
https://www.readbyqxmd.com/read/28747499/effects-of-inner-nuclear-membrane-proteins-sun1-unc-84a-and-sun2-unc-84b-on-the-early-steps-of-hiv-1-infection
#18
Torsten Schaller, Lorenzo Bulli, Darja Pollpeter, Gilberto Betancor, Juliane Kutzner, Luis Apolonia, Nikolas Herold, Robin Burk, Michael H Malim
Human immunodeficiency virus type 1 (HIV-1) infection of dividing and nondividing cells involves regulatory interactions with the nuclear pore complex (NPC), followed by translocation to the nucleus and preferential integration into genomic areas in proximity to the inner nuclear membrane (INM). To identify host proteins that may contribute to these processes, we performed an overexpression screen of known membrane-associated NE proteins. We found that the integral transmembrane proteins SUN1/UNC84A and SUN2/UNC84B are potent or modest inhibitors of HIV-1 infection, respectively, and that suppression corresponds to defects in the accumulation of viral cDNA in the nucleus...
October 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28729543/evaluation-of-atm-heterozygous-mutations-underlying-individual-differences-in-radiosensitivity-using-genome-editing-in-human-cultured-cells
#19
Ekaterina Royba, Tatsuo Miyamoto, Silvia Natsuko Akutsu, Kosuke Hosoba, Hiroshi Tauchi, Yoshiki Kudo, Satoshi Tashiro, Takashi Yamamoto, Shinya Matsuura
Ionizing radiation (IR) induces DNA double-strand breaks (DSBs), which are an initial step towards chromosomal aberrations and cell death. It has been suggested that there are individual differences in radiosensitivity within human populations, and that the variations in DNA repair genes might determine this heterogeneity. However, it is difficult to quantify the effect of genetic variants on the individual differences in radiosensitivity, since confounding factors such as smoking and the diverse genetic backgrounds within human populations affect radiosensitivity...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28701426/dynamics-of-in-vivo-asc-speck-formation
#20
Paola Kuri, Nicole L Schieber, Thomas Thumberger, Joachim Wittbrodt, Yannick Schwab, Maria Leptin
Activated danger or pathogen sensors trigger assembly of the inflammasome adaptor ASC into specks, large signaling platforms considered hallmarks of inflammasome activation. Because a lack of in vivo tools has prevented the study of endogenous ASC dynamics, we generated a live ASC reporter through CRISPR/Cas9 tagging of the endogenous gene in zebrafish. We see strong ASC expression in the skin and other epithelia that act as barriers to insult. A toxic stimulus triggered speck formation and rapid pyroptosis in keratinocytes in vivo...
September 4, 2017: Journal of Cell Biology
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