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Jorge L Rosas-Trigueros
Bax is a protein that promotes apoptosis (a form of cell death). The atomistic details of the mechanism by which Bax is activated during apoptosis remain a subject of debate. C-terminal basic residues in the sequence of Bax show remarkable conservation across a variety of species. The role of these charged residues in the stability of Bax was investigated by submitting substituted mutants to molecular dynamics simulations at high temperatures. Mutation of either or both K189 and K190 led to dramatic changes in helical content, radius of gyration, proximity of the C terminus to the core of the protein, exposure of the BH3 domain, and bundling of the core...
October 2016: FEBS Open Bio
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 19, 2016: Nature
Vicente Andreu-Fernandez, Maria J García-Murria, Manuel Bañó-Polo, Juliette Martin, Luca Monticelli, Mar Orzáez, Ismael Mingarro
Changes in the equilibrium of pro- and anti-apoptotic members of the B-cell lymphoma-2 (Bcl-2) protein family in the mitochondrial outer membrane (MOM) induce structural changes that commit cells to apoptosis. Bcl-2 homology-3 (BH3)-only proteins participate in this process by either activating pro-apoptotic effectors or inhibiting anti-apoptotic components and by promoting MOM permeabilization. The association of BH3-only proteins with MOMs is necessary for the activation and amplification of death signals; however, the nature of this association remains controversial, as these proteins lack a canonical transmembrane sequence...
October 7, 2016: Journal of Biological Chemistry
Jeremy L Yap, Lijia Chen, Maryanna E Lanning, Steven Fletcher
A hallmark of cancer is the evasion of apoptosis, which is often associated with the upregulation of the anti-apoptotic members of the Bcl-2 family of proteins. The prosurvival function of the anti-apoptotic Bcl-2 proteins is manifested by capturing the pro-apoptotic Bcl-2 proteins through their BH3 death domains. Accordingly, strategies to antagonize the anti-apoptotic Bcl-2 proteins have largely focused on the development of low-molecular-weight, synthetic and selective BH3 mimetics ("magic bullets") to disrupt the protein-protein interactions between anti- and pro-apoptotic Bcl-2 proteins...
October 17, 2016: Journal of Medicinal Chemistry
Fabio Arturo Grieco, Guido Sebastiani, Jonas Juan-Mateu, Olatz Villate, Laura Marroqui, Laurence Ladrière, Ksenya Tugay, Romano Regazzi, Marco Bugliani, Piero Marchetti, Francesco Dotta, Décio L Eizirik
Type 1 Diabetes is an autoimmune disease leading to beta cell destruction. MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression and organ formation. They participate in the pathogenesis of several autoimmune diseases, but the nature of miRNAs contributing to beta cell death in T1D and their target genes remain to be clarified.We performed a miRNA expression profile on human islet preparations exposed to the cytokines IL-1β+IFN-γ. Confirmation of miRNAs and target genes modification in human beta cells was performed by real-time qPCR...
October 13, 2016: Diabetes
Jiabing Shen, Xiaomei Chen, Hongmei Li, Yang Wang, Keke Huo, Kaifu Ke
Recently, NIX, a pro-apoptotic BH3-only protein, was found to be a novel p75 neurotrophin receptor (p75(NTR)) binding protein by screening a human fetal brain two-hybrid library in our laboratory. We further study the interaction of these two proteins and the possible roles of p75(NTR) and NIX in intracerebral hemorrhage (ICH)-induced neuronal death. Using the split-ubiquitin yeast two-hybrid system, we found that the "Copper" domain in p75(NTR) and the TM region in NIX were sufficient for the interaction of these two proteins...
October 10, 2016: Cell and Tissue Research
Rahul Sampath, Nathan W Cummins, Andrew D Badley
HIV cure is now the focus of intense research after Timothy Ray Brown (the Berlin patient) set the precedent of being the first and only person cured. A major barrier to achieving this goal on a meaningful scale is an elimination of the latent reservoir, which is thought to comprise CD4-positive cells that harbor integrated, replication-competent HIV provirus. These cells do not express viral proteins, are indistinguishable from uninfected CD4 cells, and are thought to be responsible for HIV viral rebound-that occurs within weeks of combination anti retroviral therapy (cART) interruption...
2016: Journal of Cell Death
Paul A Sibbald
Phosphine-borane adducts are a well-known moiety in synthetic and coordination chemistry. These complexes form a dative bond in which the Lewis basic phosphorus atom donates electron density into an empty p-orbital of the Lewis acidic boron atom. However, donation of the phosphorus lone pair is not the only stabilizing interaction, as hyperconjugation and electrostatic interaction also play important roles in bonding. This paper describes a detailed density functional theory level (B3LYP) study completed to determine the impact electron-donating and withdrawing substituents have on phosphine-borane bonds through the investigation of a series of para-substituted PAr3-BH3 and PH3-BAr3 phosphine-borane adducts...
November 2016: Journal of Molecular Modeling
Yaping Zhong, Yonggang Zhang, Ping Wang, Hongxiu Gao, Chunling Xu, Hui Li
Multiple myeloma (MM) is a fatal hematological cancer characterized by clonal plasma cell proliferation in the bone marrow. MM has an increasing global incidence and a poor prognosis. There are limited treatment options available for MM, and this is further compounded by the development of drug resistance. The present study demonstrated that 7-{4-[Bis-(2-hydroxyethyl)-amino]-butoxy}-5-hydroxy-8-methoxy-2-phenylchromen-4-one (V8), a novel synthetic flavonoid, induced apoptosis in human MM RPMI 8226 cells in a dose- and time-dependent manner, using cell viability assays and flow cytometry...
October 2016: Oncology Letters
Isabelle Duroux-Richard, Christine Roubert, Meryem Ammari, Jessy Présumey, Joachim R Grün, Thomas Häupl, Andreas Grützkau, Charles-Henri Lecellier, Valérie Boitez, Patrice Codogno, Johanna Escoubet, Yves-Marie Pers, Christian Jorgensen, Florence Apparailly
Metabolic changes drive monocyte differentiation and fate. Although abnormal mitochondria metabolism and innate immune responses participate in the pathogenesis of many inflammatory disorders, molecular events regulating mitochondrial activity to control life and death in monocytes remain poorly understood. We show here that, in the human monocytes, miR-125b attenuates the mitochondrial respiration through the silencing of the BH3-only pro-apoptotic protein BIK and promotes the elongation of mitochondrial network through the targeting of the mitochondrial fission process 1 protein MTP18, leading to apoptosis...
October 4, 2016: Blood
Ting Song, Ziqian Wang, Fangling Ji, Yingang Feng, Yudan Fan, Gaobo Chai, Xiangqian Li, Zhiqiang Li, Zhichao Zhang
By means of limited proteolysis assay, three-dimensional NMR, X-ray crystallography and alanine mutations, a dynamic region at the Q221R222N223 motif in the Bcl-2 homology 3 (BH3) domain of Mcl-1 has been identified as a conformational switch which controls Mcl-1 ubiquitination. Noxa(BH3) binding biases the QRN motif toward a helical conformation, thus leading to an enhanced in vitro ubiquitination of Mcl-1. In contrast, Bim(BH3) binding biases the QRN motif toward a nonhelical conformation, thus leading to the inhibition of ubiquitination...
October 4, 2016: Angewandte Chemie
Lisa M Greene, Seema M Nathwani, Daniela M Zisterer
T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive hematopoietic malignancy prone to relapse and drug resistance. Half of all T-ALL patients exhibit mutations in Notch1, which leads to aberrant Notch1 associated signaling cascades. Notch1 activation is mediated by the γ-secretase cleavage of the Notch1 receptor into the active intracellular domain of Notch1 (NCID). Clinical trials of γ-secretase small molecule inhibitors (GSIs) as single agents for the treatment of T-ALL have been unsuccessful...
October 2016: Oncology Letters
Patricia Gomez-Bougie, Maxime Halliez, Philippe Moreau, Catherine Pellat-Deceunynck, Martine Amiot
As myeloma cells actively produce and secrete immunoglobulins, they are prone to ER stress, which if unresolved leads to apoptosis. We found that myeloma cell death induced by the ER stressor Thapsigargin was highly variable, ranging from 2 to 89%. Induction of ATF4 and CHOP was observed in myeloma cells under Thapsigargin independently of cell death. The decrease in Mcl-1 was associated with protein translation inhibition and identified as a crucial factor in Thapsigargin sensitivity, since it was the only Bcl-2 family protein differentially modified between sensitive and resistant myeloma cells...
September 30, 2016: Cancer Letters
Gilad Itchaki, Jennifer R Brown
Venetoclax (VEN, ABT-199/GDC-0199) is an orally bioavailable BH3-mimetic that specifically inhibits the anti-apoptotic B-cell lymphoma/leukemia 2 (BCL2) protein. Although BCL2 overexpression is not genetically driven in chronic lymphocytic leukemia (CLL), it is nearly universal and represents a highly important and prevalent mechanism of apoptosis evasion, making it an attractive therapeutic target. This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data regarding the effectiveness and safety of VEN...
October 2016: Therapeutic Advances in Hematology
Leona Rohrbeck, Jia-Nan Gong, Erinna F Lee, Andrew J Kueh, Andreas Behren, Lin Tai, Guillaume Lessene, David C S Huang, Walter D Fairlie, Andreas Strasser, Marco J Herold
A large proportion of melanomas harbour the activating BRAF(V600E) mutation that renders these cells dependent on MAPK signalling for their survival. Although the highly specific and clinically approved BRAF(V600E) kinase inhibitor, PLX4032, induces apoptosis of melanoma cells bearing this mutation, the underlying molecular mechanisms are not fully understood. Here, we reveal that PLX4032-induced apoptosis depends on the induction of the pro-apoptotic BH3-only protein PUMA with a minor contribution of its relative BIM...
September 30, 2016: Cell Death and Differentiation
Victor Peperzak, Erik Slinger, Johanna Ter Burg, Eric Eldering
For successful treatment of malignant B-cells it is crucial to understand intrinsic survival requirements in relation to their normal progenitors. Long-lived humoral immunity as well as most B-cell malignancies, originate in the germinal center (GC). Murine GC B-cells depend on pro-survival protein MCL-1, but not BCL-XL. In contrast, naive and memory B-cells depend on BCL-2, but not BCL-XL or MCL-1. For human B-cell subsets, the functional relationships among BCL-2 members are unclear, and also if and how they shift after malignant transformation...
September 30, 2016: Cell Death and Differentiation
Camila Rubio-Patiño, Jozef P Bossowski, Elodie Villa, Laura Mondragón, Barbara Zunino, Emma Proïcs, Johanna Chiche, Frédéric Bost, Els Verhoeyen, Jean-Ehrland Ricci
Overexpression of Mcl-1 is implicated in resistance of several cancers to chemotherapeutic treatment, therefore identifying a safe way to decrease its expression in tumor cells represents a central goal. We investigated if a modulation of the diet could impact on Mcl-1 expression using a Myc-driven lymphoma model. We established that a partial reduction of caloric intake by 25% represents an efficient way to decrease Mcl-1 expression in tumor cells. Furthermore, using isocaloric custom diets, we observed that carbohydrates (CHO) are the main regulators of Mcl-1 expression within the food...
September 28, 2016: Oncotarget
L Yang
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
Heidi Gytz, Mariann F Hansen, Signe Skovbjerg, Anders C M Kristensen, Sofie Hørlyck, Mette B Jensen, Marlene Fredborg, Lotte D Markert, Nigel A McMillan, Erik I Christensen, Pia M Martensen
BACKGROUND INFORMATION: Interferons are a family of cytokines with growth inhibitory and antiviral functions, which exert their biological actions through the expression of Interferon Stimulated Genes, ISGs. The human ISG12 family of proteins comprises ISG12A, ISG12B, ISG12C and ISG6-16. Due to differential splicing and a gene variation, the human ISG12A protein exists as a full-length ISG12A form and three ISG12A variants. ISG12 has been found transcriptionally dysregulated in many disorders...
September 27, 2016: Biology of the Cell
Monica Benvenuto, Rosanna Mattera, Laura Masuelli, Gloria Taffera, Orlando Andracchio, Ilaria Tresoldi, Paolo Lido, Maria Gabriella Giganti, Justyna Godos, Andrea Modesti, Roberto Bei
Racemic Gossypol [(±)-GOS], composed of both (-)-GOS and (+)-GOS, is a small BH3-mimetic polyphenol derived from cotton seeds. (±)-GOS has been employed and well tolerated by cancer patients. Head and neck carcinoma (HNC) represents one of the most fatal cancers worldwide, and a significant proportion of HNC expresses high levels of antiapoptotic Bcl-2 proteins. In this study, we demonstrate that (±)-GOS inhibits cell proliferation and induces apoptosis and autophagy of human pharynx, tongue, and salivary gland cancer cell lines and of mouse salivary gland cancer cells (SALTO)...
September 27, 2016: International Journal of Food Sciences and Nutrition
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