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https://www.readbyqxmd.com/read/28723893/in-vivo-crispr-screening-identifies-ptpn2-as-a-cancer-immunotherapy-target
#1
Robert T Manguso, Hans W Pope, Margaret D Zimmer, Flavian D Brown, Kathleen B Yates, Brian C Miller, Natalie B Collins, Kevin Bi, Martin W LaFleur, Vikram R Juneja, Sarah A Weiss, Jennifer Lo, David E Fisher, Diana Miao, Eliezer Van Allen, David E Root, Arlene H Sharpe, John G Doench, W Nicholas Haining
Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy...
July 19, 2017: Nature
https://www.readbyqxmd.com/read/28723560/crkl-mediates-p110%C3%AE-dependent-pi3k-signaling-in-pten-deficient-cancer-cells
#2
Jing Zhang, Xueliang Gao, Fabienne Schmit, Guillaume Adelmant, Michael J Eck, Jarrod A Marto, Jean J Zhao, Thomas M Roberts
The p110β isoform of PI3K is preferentially activated in many tumors deficient in the phosphatase and tensin homolog (PTEN). However, the mechanism(s) linking PTEN loss to p110β activation remain(s) mysterious. Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation. In contrast, CRKL depletion does not impair p110α-mediated signaling. Further study showed that CRKL binds to tyrosine-phosphorylated p130Cas in PTEN-null cancer cells...
July 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28722226/biology-of-slac1-type-anion-channels-from-nutrient-uptake-to-stomatal-closure
#3
REVIEW
Rainer Hedrich, Dietmar Geiger
Contents 1 I. 1 II. 2 III. 5 IV. 8 V. 11 VI. 12 13 13 References 13 SUMMARY: Stomatal guard cells control leaf CO2 intake and concomitant water loss to the atmosphere. When photosynthetic CO2 assimilation is limited and the ratio of CO2 intake to transpiration becomes suboptimal, guard cells, sensing the rise in CO2 concentration in the substomatal cavity, deflate and the stomata close. Screens for mutants that do not close in response to experimentally imposed high CO2 atmospheres identified the guard cell-expressed Slowly activating anion channel, SLAC1, as the key player in the regulation of stomatal closure...
July 19, 2017: New Phytologist
https://www.readbyqxmd.com/read/28720849/melatonin-promotes-osteoblast-differentiation-by-regulating-osterix-protein-stability-and-expression
#4
Younho Han, Young-Mi Kim, Hyung Sik Kim, Kwang Youl Lee
Although the biological role of melatonin in osteogenic differentiation has been suggested, the mechanism of osteoblast differentiation remains unclear. Thus, the present study investigated the underlying molecular mechanisms based on osteoblast-specific transcription factors. We found that melatonin enhanced BMP-4-induced osteogenic differentiation and increased the expression of osteogenic markers, especially Osterix, which is an essential transcription factor for the differentiation of preosteoblasts into mature osteoblasts in the late stage of osteoblast differentiation...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28720772/blockade-of-axl-signaling-ameliorates-hpv16e6-mediated-tumorigenecity-of-cervical-cancer
#5
Eun-Hee Lee, Kon-Young Ji, Eun-Mi Kim, Su-Man Kim, Hyeong-Woo Song, Ha-Rim Choi, Byung Yeoup Chung, Hyo Jin Choi, Hyoung-Woo Bai, Hyung-Sik Kang
Axl receptor tyrosine kinase is involved in the tumorigenesis and metastasis of many cancers. Axl expression was markedly higher in human papilloma virus type 16E6 (HPV16E6)-overexpressing HeLa (HE6F) cells and lower in HPV16E6-suppressing CaSki (CE6R) cells than in the controls. SiRNA-mediated knockdown of E6 expression led to increased phosphatase and tensin homolog (PTEN) phosphorylation at Ser380 and attenuated AKT phosphorylation. Expression of membrane-associated guanylate kinase inverted-2 (MAGI-2), an E6-induced degradation target, was induced in E6-siRNA-transfected cells...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28720534/tgf-%C3%AE-signaling-regulates-p-akt-levels-via-pp2a-during-diapause-entry-in-the-cotton-bollworm-helicoverpa-armigera
#6
Hai-Yin Li, Tao Wang, Yong-Pan Yang, Shao-Lei Geng, Wei-Hua Xu
Akt, which is a key kinase in the insulin signaling pathway, plays important roles in glucose metabolism, cell proliferation, transcription and cell migration. Our previous studies indicated that low insulin levels and high p-Akt levels are present in diapause-destined individuals. Here, we show that PI3K, which is upstream of Akt, is low in diapause-destined pupal brains but high in p-Akt levels, implying that p-Akt is modified by factors other than the insulin signaling pathway. Protein phosphatase 2A (PP2A), which is a key regulator in the TGF-β signaling pathway, can directly bind to and dephosphorylate Akt...
July 15, 2017: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28717991/prolonged-bed-rest-impairs-rapid-cpi-17-phosphorylation-and-contraction-in-rat-mesenteric-resistance-arteries-to-cause-orthostatic-hypotension
#7
Toshio Kitazawa, Kazuyo Kitazawa
Prolonged bed rest (PBR) causes orthostatic hypotension (OH). Rapid constriction of splanchnic resistance arteries in response to a sudden increase in sympathetic tone contributes to the recovery of orthostatic arterial pressure upon standing. However, the molecular mechanism of PBR-induced dysfunction in arterial constriction is not fully understood. Previously, we showed that CPI-17, a regulatory protein for myosin phosphatase, mediates α1A-adrenergic receptor-induced rapid contraction of small mesenteric arteries...
July 17, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28717008/the-cardiac-z-disc-protein-cefip-regulates-cardiomyocyte-hypertrophy-by-modulating-calcineurin-signaling
#8
Franziska Dierck, Christian Kuhn, Claudia Rohr, Susanne Hille, Julia Braune, Samuel Sossalla, Sibylle Molt, Peter F M van der Ven, Dieter O Fürst, Norbert Frey
The z-disc is a structural component at the lateral borders of the sarcomere and is important for mechanical stability and contractility of both cardiac and skeletal muscles. Of note, the sarcomeric z-disc also represents a nodal point in cardiomyocyte function and signaling. Mutations of numerous z-disc proteins are associated with cardiomyopathies and muscle diseases. To identify additional z-disc proteins that might contribute to cardiac disease, we employed an in silico screen for cardiac-enriched cDNAs...
July 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28716125/mercury-alters-endogenous-phosphorylation-profiles-of-syk-in-murine-b-cells
#9
Joseph A Caruso, Nicholas Carruthers, Namhee Shin, Randal Gill, Paul M Stemmer, Allen Rosenspire
BACKGROUND: Epidemiological evidence and animal models suggest that exposure to low and non-neurotoxic concentrations of mercury may contribute to idiosyncratic autoimmune disease. Since defects in function and signaling in B cells are often associated with autoimmunity, we investigated whether mercury exposure might alter B cell responsiveness to self-antigens by interfering with B cell receptor (BCR) signal transduction. In this study we determined the effects of mercury on the protein tyrosine kinase SYK, a critical protein involved in regulation of the BCR signaling pathway...
July 17, 2017: BMC Immunology
https://www.readbyqxmd.com/read/28716058/srf-modulates-seizure-occurrence-activity-induced-gene-transcription-and-hippocampal-circuit-reorganization-in-the-mouse-pilocarpine-epilepsy-model
#10
Pascal Lösing, Cristina Elena Niturad, Merle Harrer, Christopher Meyer Zu Reckendorf, Theresa Schatz, Daniela Sinske, Holger Lerche, Snezana Maljevic, Bernd Knöll
A hallmark of temporal lobe epilepsy (TLE) is hippocampal neuronal demise and aberrant mossy fiber sprouting. In addition, unrestrained neuronal activity in TLE patients induces gene expression including immediate early genes (IEGs) such as Fos and Egr1.We employed the mouse pilocarpine model to analyze the transcription factor (TF) serum response factor (SRF) in epileptogenesis, seizure induced histopathology and IEG induction. SRF is a neuronal activity regulated TF stimulating IEG expression as well as nerve fiber growth and guidance...
July 17, 2017: Molecular Brain
https://www.readbyqxmd.com/read/28713993/gene-microarray-analysis-of-expression-profiles-in-liver-ischemia-and-reperfusion
#11
Xiaoyang Zheng, Huaqiang Zhou, Zeting Qiu, Shaowei Gao, Zhongxing Wang, Liangcan Xiao
Liver ischemia and reperfusion (I/R) injury is of primary concern in cases of liver disease worldwide and is associated with hemorrhagic shock, resection and transplantation. Numerous studies have previously been conducted to investigate the underlying mechanisms of liver I/R injury, however these have not yet been fully elucidated. To determine the difference between ischemia and reperfusion in signaling pathways and the relative pathological mechanisms, the present study downloaded microarray data GSE10657 from the Gene Expression Omnibus database...
July 13, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28713988/coronin-3-negatively-regulates-g6pc3-in-hepg2-cells-as-identified-by-label%C3%A2-free-mass%C3%A2-spectrometry
#12
Yunzhen Gao, Ling Li, Xiaohua Xing, Minjie Lin, Yongyi Zeng, Xiaolong Liu, Jingfeng Liu
Human coronin 3 is involved in many types of cancers, but the underlying molecular mechanisms require further elucidation. The present study demonstrated that coronin 3 is significantly upregulated in clinical primary hepatocellular carcinoma (HCC) samples by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemical staining. Subsequently, proteins that were regulated by coronin 3 in both coronin 3 overexpressing or knocked down HepG2 cells were analyzed by label free mass spectrometry; overall, 249 proteins were identified to be closely regulated by coronin 3, and those coronin 3 regulated proteins were enriched in cellular, physiological and metabolism processes...
July 15, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28713969/downregulation-of-ptprh-sap-1-in-colorectal-tumors
#13
Mateusz Bujko, Paulina Kober, Małgorzata Statkiewicz, Michal Mikula, Emilia Grecka, Nataliia Rusetska, Marcin Ligaj, Jerzy Ostrowski, Janusz Aleksander Siedlecki
Tyrosine phosphorylation is one of the basic mechanisms for signal transduction in the cell. Receptors exhibiting tyrosine kinase activity are widely involved in carcinogenesis and are negatively regulated by receptor protein tyrosine phosphatases (RPTP). Genes encoding different RPTPs are affected by aberrant epigenetic regulation in cancer. PTPRH (SAP-1) has been previously described to be overexpressed in colorectal cancer (CRC) and classified as an oncogenic factor. Previous microarray-based mRNA expression comparison of colorectal adenomas (AD), CRC and normal mucosa samples (NM) demonstrated that PTPRH tumor expression is the most reduced of all RPTP genes...
July 5, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28713240/the-coordinated-action-of-calcineurin-and-cathepsin-d-protects-against-%C3%AE-synuclein-toxicity
#14
Andreas Aufschnaiter, Lukas Habernig, Verena Kohler, Jutta Diessl, Didac Carmona-Gutierrez, Tobias Eisenberg, Walter Keller, Sabrina Büttner
The degeneration of dopaminergic neurons during Parkinson's disease (PD) is intimately linked to malfunction of α-synuclein (αSyn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of αSyn has been attributed to disturbances in several biological processes conserved from yeast to humans, including Ca(2+) homeostasis, general lysosomal function and autophagy. However, the precise sequence of events that eventually results in cell death remains unclear...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28713017/intracellular-co-delivery-of-sr-ion-and-phenamil-drug-through-mesoporous-bioglass-nanocarriers-synergizes-bmp-signaling-and-tissue-mineralization
#15
Jung-Hwan Lee, Nandin Mandakhbayar, Ahmed El-Fiqi, Haw-Won Kim
Inducing differentiation and maturation of resident multipotent stem cells (MSCs) is an important strategy to regenerate hard tissues in mal-calcification conditions. Here we explore a co-delivery approach of therapeutic molecules comprised of ion and drug through a mesoporous bioglass nanoparticle (MBN) for this purpose. Recently, MBN has offered unique potential as a nanocarrier for hard tissues, in terms of high mesoporosity, bone bioactivity (and possibly degradability), tunable delivery of biomolecules, and ionic modification...
July 13, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28711506/sodium-selenate-activated-wnt-%C3%AE-catenin-signaling-and-repressed-amyloid-%C3%AE-formation-in-a-triple-transgenic-mouse-model-of-alzheimer-s-disease
#16
Na Jin, Huazhang Zhu, Xiao Liang, Wei Huang, Qingguo Xie, Peng Xiao, Jiazuan Ni, Qiong Liu
Accumulating evidences show that selenium dietary intake is inversely associated with the mortality of Alzheimer's disease (AD). Sodium selenate has been reported to reduce neurofibrillary tangles (NFT) in the tauopathic mouse models, but its effects on the Wnt/β-catenin signaling pathway and APP processing remain unknown during AD formation. In this paper, triple transgenic AD mice (3×Tg-AD) had been treated with sodium selenate in drinking water for 10month before the detection of hippocampal pathology...
July 12, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28710354/ssu72-attenuates-autoimmune-arthritis-via-targeting-of-stat3-signaling-and-th17-activation
#17
Seung Hoon Lee, Eun-Kyung Kim, Jeong-Eun Kwon, Jin-Kwan Lee, DoHyeong Lee, Se-Young Kim, Hyeon-Beom Seo, Hyun Sik Na, KyoungAh Jung, Seung-Ki Kwok, Chang-Woo Lee, Sung-Hwan Park, Mi-La Cho
Signal transducer and activator of transcription 3 (STAT3) orchestrates the differentiation of several cell types, including interleukin-17 (IL-17)-releasing Th17 cells. Dysregulation of Th17 cells results in chronic inflammatory responses. Ssu72 is a C-terminal domain phosphatase required for transcriptional regulation. However, the mechanism by which Ssu72 affects STAT3 activation and Th17 cell differentiation is unclear. Here, we found that Ssu72 overexpression suppresses STAT3 activation and Th17 cell responses in vitro...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28709835/the-antimicrobial-peptide-human-%C3%AE-defensin-1-potentiates-in-vitro-osteoclastogenesis-via-activation-of-the-p44-42-mitogen-activated-protein-kinases
#18
Anupong Makeudom, Chayarop Supanchart, Pattanin Montreekachon, Sakornrat Khongkhunthian, Thanapat Sastraruji, Julaporn Krisanaprakornkit, Suttichai Krisanaprakornkit
Previous studies have demonstrated increased expression and raised levels of human β-defensin (hBD)-1 in gingival tissue and crevicular fluid of patients with chronic periodontitis and peri-implantitis, oral bone-resorbing diseases caused by enhanced osteoclastogenesis. Therefore, we aimed to investigate the effect of hBD-1 on osteoclast formation and function and to elucidate the involved signaling pathway in vitro. Human peripheral blood mononuclear cells (PBMCs) were first incubated with various doses of hBD-1 and cell viability was assayed by MTT...
July 11, 2017: Peptides
https://www.readbyqxmd.com/read/28706187/delay-of-germination1-requires-pp2c-phosphatases-of-the-aba-signalling-pathway-to-control-seed-dormancy
#19
Guillaume Née, Katharina Kramer, Kazumi Nakabayashi, Bingjian Yuan, Yong Xiang, Emma Miatton, Iris Finkemeier, Wim J J Soppe
The time of seed germination is a major decision point in the life of plants determining future growth and development. This timing is controlled by seed dormancy, which prevents germination under favourable conditions. The plant hormone abscisic acid (ABA) and the protein DELAY OF GERMINATION 1 (DOG1) are essential regulators of dormancy. The function of ABA in dormancy is rather well understood, but the role of DOG1 is still unknown. Here, we describe four phosphatases that interact with DOG1 in seeds. Two of them belong to clade A of type 2C protein phosphatases: ABA-HYPERSENSITIVE GERMINATION 1 (AHG1) and AHG3...
July 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28706133/serine-arginine-protein-kinase-1-srpk1-is-elevated-in-gastric-cancer-and-plays-oncogenic-functions
#20
Xiaotao Xu, Yuehua Wei, Shidong Wang, Man Luo, Heng Zeng
Serine-arginine protein kinase 1 (SRPK1) phosphorylates proteins involved in the regulation of several mRNA processing pathways including alternative splicing. SRPK1 has been reported to be over-expressed in multiple cancers including prostate, breast, lung and glioma. Several studies further identified that inhibition of SRPK1 showed tumor-suppressive effects, thus raising SRPK1 as a novel candidate chemotherapy target. Interestingly, SRPK1 plays tumor suppressing role in mouse embryonic fibroblasts, on that SRPK1-silencing induces cell transformation...
June 28, 2017: Oncotarget
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