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https://www.readbyqxmd.com/read/28057804/cell-cycle-progression-dictates-the-requirement-for-bcl2-in-natural-killer-cell-survival
#1
Charlotte Viant, Sophie Guia, Robert J Hennessy, Jai Rautela, Kim Pham, Claire Bernat, Wilford Goh, Yuhao Jiao, Rebecca Delconte, Michael Roger, Vanina Simon, Fernando Souza-Fonseca-Guimaraes, Stephanie Grabow, Gabrielle T Belz, Benjamin T Kile, Andreas Strasser, Daniel Gray, Phillip D Hodgkin, Bruce Beutler, Eric Vivier, Sophie Ugolini, Nicholas D Huntington
Natural killer (NK) cells are innate lymphoid cells with antitumor functions. Using an N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a strain with an NK cell deficiency caused by a hypomorphic mutation in the Bcl2 (B cell lymphoma 2) gene. Analysis of these mice and the conditional deletion of Bcl2 in NK cells revealed a nonredundant intrinsic requirement for BCL2 in NK cell survival. In these mice, NK cells in cycle were protected against apoptosis, and NK cell counts were restored in inflammatory conditions, suggesting a redundant role for BCL2 in proliferating NK cells...
January 5, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28053206/gsk3b-mediated-phosphorylation-of-mcl1-regulates-axonal-autophagy-to-promote-wallerian-degeneration
#2
Shuji Wakatsuki, Shinji Tokunaga, Megumi Shibata, Toshiyuki Araki
Macroautophagy is a catabolic process, in which portions of cytoplasm or organelles are delivered to lysosomes for degradation. Emerging evidence has indicated a pathological connection between axonal degeneration and autophagy. However, the physiological function and induction mechanism of autophagy in axons remain elusive. We herein show that, through activation of BECLIN1, glycogen synthase kinase 3B (GSK3B)-mediated phosphorylation of BCL2 family member MCL1 induces axonal autophagy and axonal degeneration...
January 4, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28039357/key-survival-factor-mcl-1-correlates-with-sensitivity-to-combined-bcl-2-bcl-xl-blockade
#3
Michelle Williams, Linus Lee, Donna J Hicks, Meghan M Joly, David Elion, Bushra Rahman, Courtney McKernan, Violeta Sanchez, Justin M Balko, Thomas Stricker, Monica Valeria Estrada, Rebecca S Cook
: An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use anti-apoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of anti-apoptotic Bcl-2 family members in clinical breast cancer datasets, revealed greater expression and more frequent gene amplification of MCL1 as compared to BCL2 or BCL2L1 (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like...
December 30, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28011486/hyperforin-inhibits-cell-growth-by-inducing-intrinsic-and-extrinsic-apoptotic-pathways-in-hepatocellular-carcinoma-cells
#4
I-Tsang Chiang, Wei-Ting Chen, Chih-Wei Tseng, Yen-Chung Chen, Yu-Cheng Kuo, Bi-Jhih Chen, Mao-Chi Weng, Hwai-Jeng Lin, Wei-Shu Wang
The aim of the present study was to investigate the antitumor effect and mechanism of action of hyperforin in hepatocellular carcinoma (HCC) SK-Hep1 cells in vitro. Cells were treated with different concentrations of hyperforin for different periods of time. Effects of hyperforin on cell viability, apoptosis signaling, and expression of anti-apoptotic and proliferative proteins [cellular FLICE-like inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), myeloid cell leukemia 1(MCL1), and cyclin-D1] were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and western blotting...
January 2017: Anticancer Research
https://www.readbyqxmd.com/read/28003334/huwe1-is-a-critical-colonic-tumour-suppressor-gene-that-prevents-myc-signalling-dna-damage-accumulation-and-tumour-initiation
#5
Kevin B Myant, Patrizia Cammareri, Michael C Hodder, Jimi Wills, Alex Von Kriegsheim, Balázs Győrffy, Mamun Rashid, Simona Polo, Elena Maspero, Lynsey Vaughan, Basanta Gurung, Evan Barry, Angeliki Malliri, Fernando Camargo, David J Adams, Antonio Iavarone, Anna Lasorella, Owen J Sansom
Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours...
December 21, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27997540/il-7-receptor-mutations-and-steroid-resistance-in-pediatric-t-cell-acute-lymphoblastic-leukemia-a-genome-sequencing-study
#6
Yunlei Li, Jessica G C A M Buijs-Gladdines, Kirsten Canté-Barrett, Andrew P Stubbs, Eric M Vroegindeweij, Willem K Smits, Ronald van Marion, Winand N M Dinjens, Martin Horstmann, Roland P Kuiper, Rogier C Buijsman, Guido J R Zaman, Peter J van der Spek, Rob Pieters, Jules P P Meijerink
BACKGROUND: Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids, which are currently the cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival and cure. However, the cellular mechanisms underlying steroid resistance in T-ALL patients are poorly understood...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27956387/targeting-sphingosine-kinase-1-induces-mcl1-dependent-cell-death-in-acute-myeloid-leukemia
#7
Jason A Powell, Alexander C Lewis, Wenying Zhu, John Toubia, Melissa R Pitman, Craig T Wallington-Beddoe, Paul A B Moretti, Diana Iarossi, Saumya E Samaraweera, Nik Cummings, Hayley S Ramshaw, Daniel Thomas, Andrew H Wei, Angel F Lopez, Richard J D'Andrea, Ian D Lewis, Stuart M Pitson
Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1-phosphate (S1P) and has established roles in tumor initiation, progression and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primary AML, however, has not been previously investigated. Here we show that SPHK1 is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells...
December 12, 2016: Blood
https://www.readbyqxmd.com/read/27939888/chaperone-mediated-autophagy-promotes-lung-cancer-cell-survival-through-selective-stabilization-of-the-pro-survival-protein-mcl1
#8
Junya Suzuki, Wataru Nakajima, Hidenori Suzuki, Yumi Asano, Nobuyuki Tanaka
Autophagy is a dynamic recycling system using lysosomal proteolysis that produces new proteins and energy for cellular renovation and homeostasis. Although macroautophagy is known to serve as a survival pathway in many cancer cells, the role of chaperone-mediated autophagy (CMA), a selective protein degradation system, in cancer is not fully understood. Here, we demonstrated that lysosomal proteolysis, but not macroautophagy, attenuated apoptosis induced by the tyrosine kinase inhibitor, crizotinib, in the non-small-cell lung cancer (NSCLC) cell line, EBC1...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27932492/novel-regulatory-roles-of-mff-and-drp1-in-e3-ubiquitin-ligase-march5-dependent-degradation-of-mid49-and-mcl1-and-control-of-mitochondrial-dynamics
#9
Edward Cherok, Shan Xu, Sunan Li, Shweta Das, W Alex Meltzer, Michal Zalzman, Chunxin Wang, Mariusz Karbowski
MARCH5, an OMM-associated E3 ubiquitin ligase, controls mitochondrial function. Despite its importance, the mechanism and factors controlling MARCH5 activity are largely unknown. Here we report that the MARCH5 C-terminal domain plays a critical role in degradation of MARCH5 substrates, likely by facilitating release of ubiquitinated proteins from the OMM. We also found that the mitochondrial fission proteins Drp1 and Mff negatively regulate MARCH5's activity toward MiD49 and Mcl1. Knockouts of either Drp1 or Mff led to reduced expression, shorter half-lives, and increased ubiquitination of MiD49 and Mcl1...
December 8, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27919953/bishydroquinone-renieramycin-m-induces-apoptosis-of-human-lung-cancer-cells-through-a-mitochondria-dependent-pathway
#10
Tatchakorn Pinkhien, Arnatchai Maiuthed, Supakarn Chamni, Khanit Suwanborirux, Naoki Saito, Pithi Chanvorachote
BACKGROUND: Renieranycin M (RM), a bistetrahydro-isoquinolinequinone isolated from the Thai blue sponge, Xestospongia sp. was reported to be a potent anti-lung cancer agent. Modification at quinone ring enhanced apoptosis over necrosis. Thus, bishydroquinone renieramycin M (HQ-RM) was prepared and evaluated for apoptosis induction in lung cancer cells. METHODS: HQ-RM was examined for cytotoxicity and apoptosis induction in human lung cancer H292 cells by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazoliumbromide and Hoechst/propidium iodide staining, respectively...
2016: Anticancer Research
https://www.readbyqxmd.com/read/27913212/vcp-cooperates-with-ubxd1-to-degrade-mitochondrial-outer-membrane-protein-mcl1-in-model-of-huntington-s-disease
#11
Xing Guo, Xin Qi
Proteasome-dependent turnover of mitochondrial outer membrane (OMM)-associated proteins is one of the mechanisms for maintaining proper mitochondrial quality and function. However, the underlying pathways and their implications in human disease are poorly understood. Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by expanded CAG repeats in the N terminal of the huntingtin gene (mutant Huntingtin, mtHtt). In this study, we show an extensive degradation of the OMM protein MCL1 (Myeloid cell leukemia sequence 1) in both HD mouse striatal cells and HD patient fibroblasts...
February 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27907212/diffuse-large-b-cell-lymphoma-cell-line-u-2946-model-for-mcl1-inhibitor-testing
#12
Hilmar Quentmeier, Hans G Drexler, Vivien Hauer, Roderick A F MacLeod, Claudia Pommerenke, Cord C Uphoff, Margarete Zaborski, Mattias Berglund, Gunilla Enblad, Rose-Marie Amini
Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma worldwide. We describe the establishment and molecular characteristics of the DLBCL cell line U-2946. This cell line was derived from a 52-year-old male with DLBCL. U-2946 cells carried the chromosomal translocation t(8;14) and strongly expressed MYC, but not the mature B-cell lymphoma associated oncogenes BCL2 and BCL6. Instead, U-2946 cells expressed the antiapoptotic BCL2 family member MCL1 which was highly amplified genomically (14n)...
2016: PloS One
https://www.readbyqxmd.com/read/27906183/male-sterility-in-mcl-1-flox-mice-is-not-due-to-enhanced-mcl1-protein-stability
#13
Casey Ah-Cann, Maximilien Tailler, Andrew J Kueh, Marco J Herold, Joseph T Opferman, Marie-Liesse Asselin-Labat, Philippe Bouillet
No abstract text is available yet for this article.
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27871464/downregulation-of-mir-29a-b-c-in-placenta-accreta-inhibits-apoptosis-of-implantation-site-intermediate-trophoblast-cells-by-targeting-mcl1
#14
Yongzhong Gu, Yuehong Bian, Xiaofei Xu, Xietong Wang, Changting Zuo, Jinlai Meng, Hongyan Li, Shigang Zhao, Yunnan Ning, Yongzhi Cao, Tao Huang, Junhao Yan, Zi-Jiang Chen
OBJECTIVE: Placenta accreta is defined as abnormal adhesion of placental villi to the uterine myometrium. Although this condition has become more common as a result of the increasing rate of cesarean sections, the underlying causative mechanism(s) remain elusive. Because microRNA-29a/b/c (miR-29a/b/c) have been shown to play important roles in placental development, this study evaluated the roles of these microRNAs in placenta accreta. METHODS: Expression of miR-29a/b/c and myeloid cell leukemia-1 (MCL1) were quantified in patient tissues and HTR8/SVneo trophoblast cells using the real-time quantitative polymerase chain reaction...
December 2016: Placenta
https://www.readbyqxmd.com/read/27815296/mcl1-can-be-targeted-to-induce-apoptosis-in-multiple-cancer-types
#15
(no author information available yet)
An MCL1 inhibitor, S63845, has antitumor activity in multiple hematologic malignancies in vivo.
December 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27807800/establishment-of-a-mirna-mrna-regulatory-network-in-metastatic-renal-cell-carcinoma-and-screening-of-potential-therapeutic-targets
#16
Jie Zhu, Xin Ma, Yu Zhang, Dong Ni, Qing Ai, Hongzhao Li, Xu Zhang
This study aimed to screen effective diagnosis or treatment biomarkers for renal cell carcinoma, especially for metastatic renal cell carcinoma (mRCC) based on microRNA (miRNA) and messenger RNA (mRNA) genechip, and their regulatory network. The differential expressions of miRNAs and mRNAs were examined by miRNA and mRNA gene-chip analyses, respectively, in patients with either localized renal cell carcinoma (lRCC) or mRCC, and a miRNA-mRNA regulatory network was established. Subsequently, the regulation of selected mRNAs by miRNAs was validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and dual-luciferase reporter gene assay...
November 2, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/27779208/racial-differences-in-microrna-and-gene-expression-in-hypertensive-women
#17
Douglas F Dluzen, Nicole Noren Hooten, Yongqing Zhang, Yoonseo Kim, Frank E Glover, Salman M Tajuddin, Kimberly D Jacob, Alan B Zonderman, Michele K Evans
Systemic arterial hypertension is an important cause of cardiovascular disease morbidity and mortality. African Americans are disproportionately affected by hypertension, in fact the incidence, prevalence, and severity of hypertension is highest among African American (AA) women. Previous data suggests that differential gene expression influences individual susceptibility to selected diseases and we hypothesized that this phenomena may affect health disparities in hypertension. Transcriptional profiling of peripheral blood mononuclear cells from AA or white, normotensive or hypertensive females identified thousands of mRNAs differentially-expressed by race and/or hypertension...
October 25, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27775704/pim1-kinase-regulates-cell-death-tumor-growth-and-chemotherapy-response-in-triple-negative-breast-cancer
#18
Fara Brasó-Maristany, Simone Filosto, Steven Catchpole, Rebecca Marlow, Jelmar Quist, Erika Francesch-Domenech, Darren A Plumb, Leila Zakka, Patrycja Gazinska, Gianmaria Liccardi, Pascal Meier, Albert Gris-Oliver, Maggie Chon U Cheang, Anna Perdrix-Rosell, Manar Shafat, Elodie Noël, Nirmesh Patel, Kristen McEachern, Maurizio Scaltriti, Pau Castel, Farzana Noor, Richard Buus, Sumi Mathew, Johnathan Watkins, Violeta Serra, Pierfrancesco Marra, Anita Grigoriadis, Andrew N Tutt
Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines...
November 2016: Nature Medicine
https://www.readbyqxmd.com/read/27773673/polo-like-kinase-1-regulates-myc-stabilization-and-activates-a-feedforward-circuit-promoting-tumor-cell-survival
#19
Daibiao Xiao, Ming Yue, Hexiu Su, Ping Ren, Jue Jiang, Feng Li, Yufeng Hu, Haining Du, Hudan Liu, Guoliang Qing
MYCN amplification in human cancers predicts poor prognosis and resistance to therapy. However, pharmacological strategies that directly target N-Myc, the protein encoded by MYCN, remain elusive. Here, we identify a molecular mechanism responsible for reciprocal activation between Polo-like kinase-1 (PLK1) and N-Myc. PLK1 specifically binds to the SCF(Fbw7) ubiquitin ligase, phosphorylates it, and promotes its autopolyubiquitination and proteasomal degradation, counteracting Fbw7-mediated degradation of N-Myc and additional substrates, including cyclin E and Mcl1...
November 3, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27760111/the-mcl1-inhibitor-s63845-is-tolerable-and-effective-in-diverse-cancer-models
#20
András Kotschy, Zoltán Szlavik, James Murray, James Davidson, Ana Leticia Maragno, Gaëtane Le Toumelin-Braizat, Maïa Chanrion, Gemma L Kelly, Jia-Nan Gong, Donia M Moujalled, Alain Bruno, Márton Csekei, Attila Paczal, Zoltán B Szabo, Szabolcs Sipos, Gábor Radics, Agnes Proszenyak, Balázs Balint, Levente Ondi, Gábor Blasko, Alan Robertson, Allan Surgenor, Pawel Dokurno, Ijen Chen, Natalia Matassova, Julia Smith, Christopher Pedder, Christopher Graham, Aurélie Studeny, Gaëlle Lysiak-Auvity, Anne-Marie Girard, Fabienne Gravé, David Segal, Chris D Riffkin, Giovanna Pomilio, Laura C A Galbraith, Brandon J Aubrey, Margs S Brennan, Marco J Herold, Catherine Chang, Ghislaine Guasconi, Nicolas Cauquil, Fabien Melchiore, Nolwen Guigal-Stephan, Brian Lockhart, Frédéric Colland, John A Hickman, Andrew W Roberts, David C S Huang, Andrew H Wei, Andreas Strasser, Guillaume Lessene, Olivier Geneste
Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway...
October 27, 2016: Nature
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