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JOURNAL ARTICLE
Annarosa Mangone, Maria Cristina Caggiani, Tiziana Forleo, Lorena Carla Giannossa, Pasquale Acquafredda
The blue color of glass and ceramic glazes produced in Apulia and Basilicata (Southern Italy) between the 13th and 14th centuries and connected to the Norman-Swabian Emperor Frederick II, has been, for a long time, under archaeometric investigation. On the one hand, it has usually been associated with lapis lazuli, due to the finding of the polysulphide blue chromophores typical of lazurite. Moreover, the observation that the mineral haüyne, which belongs to the sodalite group as well as lazurite, can be blue and/or can gain a blue color after heating, due to the same chromophores, has caused this automatic attribution to be questioned, and also considering that the mineral is characteristic of the rock haüynophyre of Melfi (Potenza, Southern Italy), a location of interest for glass and pottery findings...
February 6, 2023: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
#42
Jesús Muñoz-Estrada, Abraham V Nguyen, Sarah C Goetz
UNLABELLED: Frameshift mutations in Tau Tubulin Kinase 2 ( TTBK2 ) cause spinocerebellar ataxia type 11 (SCA11), which is characterized by the progressive loss of Purkinje cells and cerebellar atrophy. Previous work showed that these TTBK2 variants generate truncated proteins that interfere with primary ciliary trafficking and with Sonic Hedgehog (SHH) signaling in mice. Nevertheless, the molecular mechanisms underlying the dominant interference of mutations remain unknown. Herein, we discover that SCA11-associated variants contain a bona fide peroxisomal targeting signal type 1...
February 1, 2023: bioRxiv
#43
JOURNAL ARTICLE
Cristina Molnar, Jose Reina, Anastasia Herrero, Jan Peter Heinen, Victoria Méndiz, Sophie Bonnal, Manuel Irimia, María Sánchez-Jiménez, Sara Sánchez-Molina, Jaume Mora, Cayetano Gonzalez
Ewing sarcoma (EwS) is a human malignant tumor typically driven by the Ewing sarcoma-Friend leukemia integration (EWS-FLI) fusion protein. A paucity of genetically modified animal models, partially owed to the high toxicity of EWS-FLI, hinders research on EwS. Here, we report a spontaneous mutant variant, EWS-FLI1FS , that circumvents the toxicity issue in Drosophila. Through proteomic and genomic analyses, we show that human EWS-FLI1FS interacts with the Drosophila homologues of EWS-FLI human protein partners, including core subunits of chromatin remodeling complexes, the transcription machinery, and the spliceosome; brings about a massive dysregulation of transcription that affects a significant fraction of known targets of EWS-FLI in human cells; and modulates splicing...
September 2022: PNAS Nexus
#44
JOURNAL ARTICLE
Oriol Fornes, Alicia Jia, Hye Sun Kuehn, Qing Min, Ulrich Pannicke, Nikolai Schleussner, Romane Thouenon, Zhijia Yu, María de Los Angeles Astbury, Catherine M Biggs, Miguel Galicchio, Jorge Alberto Garcia-Campos, Silvina Gismondi, Guadalupe Gonzalez Villarreal, Kyla J Hildebrand, Manfred Hönig, Jia Hou, Despina Moshous, Stefania Pittaluga, Xiaowen Qian, Jacob Rozmus, Ansgar S Schulz, Aidé Tamara Staines-Boone, Bijun Sun, Jinqiao Sun, Schauer Uwe, Edna Venegas-Montoya, Wenjie Wang, Xiaochuan Wang, Wenjing Ying, Xiaowen Zhai, Qinhua Zhou, Altuna Akalin, Isabelle André, Thomas F E Barth, Bernd Baumann, Anne Brüstle, Gaetan Burgio, Jacinta C Bustamante, Jean-Laurent Casanova, Marco G Casarotto, Marina Cavazzana, Loïc Chentout, Ian A Cockburn, Mariantonia Costanza, Chaoqun Cui, Oliver Daumke, Kate L Del Bel, Hermann Eibel, Xiaoqian Feng, Vedran Franke, J Christof M Gebhardt, Andrea Götz, Stephan Grunwald, Bénédicte Hoareau, Timothy R Hughes, Eva-Maria Jacobsen, Martin Janz, Arttu Jolma, Chantal Lagresle-Peyrou, Nannan Lai, Yaxuan Li, Susan Lin, Henry Y Lu, Saul O Lugo-Reyes, Xin Meng, Peter Möller, Nidia Moreno-Corona, Julie E Niemela, Gherman Novakovsky, Jareb J Perez-Caraballo, Capucine Picard, Lucie Poggi, Maria-Emilia Puig-Lombardi, Katrina L Randall, Anja Reisser, Yohann Schmitt, Sandali Seneviratne, Mehul Sharma, Jennifer Stoddard, Srinivasan Sundararaj, Harry Sutton, Linh Q Tran, Ying Wang, Wyeth W Wasserman, Zichao Wen, Wiebke Winkler, Ermeng Xiong, Ally W H Yang, Meiping Yu, Lumin Zhang, Hai Zhang, Qian Zhao, Xin Zhen, Anselm Enders, Sven Kracker, Ruben Martinez-Barricarte, Stephan Mathas, Sergio D Rosenzweig, Klaus Schwarz, Stuart E Turvey, Ji-Yang Wang
Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii , and presented with agammaglobulinemia. Patients' B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced TH 17 and TFH populations and exhibited decreased cytokine production...
January 20, 2023: Science Immunology
#45
JOURNAL ARTICLE
Jerome Fortin, Ming-Feng Chiang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Julie Leca, François Lemonnier, Wanda Y Li, Miki S Gams, Takashi Sakamoto, Mandy Chu, Chantal Tobin, Eric Laugesen, Troy M Robinson, Annick You-Ten, Daniel J Butler, Thorsten Berger, Mark D Minden, Ross L Levine, Cynthia J Guidos, Ari M Melnick, Christopher E Mason, Tak W Mak
Mutations in IDH1, IDH2 , and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1 , IDH2 , and TET2 mutations may converge on a common oncogenic mechanism...
January 24, 2023: Proceedings of the National Academy of Sciences of the United States of America
#46
JOURNAL ARTICLE
Hang Yuan, Qi Kang, Zhehui Li, Xuanxuan Bai, Jianxin Jia, Daxiong Han, Xijie Wu, Mingyu Li
Glucagon receptor plays an important role in the regulation of glucose metabolism. Studies have revealed that glucagon receptor antagonism is a potential effective treatment for diabetes. However, the functions of GCGR have not been fully illustrated. Although two Gcgr truncation knockout mice models have been widely used for GCGR function studies, truncated gene may remain neomorphic and/or dominant-negative function. In this study, we took the advantages of Crispr-Cas9 technique and generated a novel allele of GCGR in the mouse that yields complete loss of GCGR protein...
December 28, 2022: Biochemical and Biophysical Research Communications
#47
JOURNAL ARTICLE
Mohammed Khurshed, Elia Prades-Sagarra, Sarah Saleh, Peter Sminia, Johanna W Wilmink, Remco J Molenaar, Hans Crezee, Cornelis J F van Noorden
Mutations in the isocitrate dehydrogenase 1 ( IDH1 MUT ) gene occur in various types of malignancies, including ~60% of chondrosarcomas, ~30% of intrahepatic cholangiocarcinomas and >80% of low-grade gliomas. IDH1 MUT are causal in the development and progression of these types of cancer due to neomorphic production of the oncometabolite D -2-hydroxyglutarate ( D -2HG). Intracellular accumulation of D -2HG has been implicated in suppressing homologous recombination and renders IDH1 MUT cancer cells sensitive to DNA-repair-inhibiting agents, such as poly-(adenosine 5'-diphosphate-ribose) polymerase inhibitors (PARPi)...
December 17, 2022: Cancers
#48
JOURNAL ARTICLE
Kaustav Mukherjee, James J Bieker
EKLF/Klf1 is a zinc-finger transcription activator essential for erythroid lineage commitment and terminal differentiation. Using ChIP-seq, we investigate EKLF DNA binding and transcription activation mechanisms during mouse embryonic erythropoiesis. We utilize the Nan/+ mouse that expresses the EKLF-E339D (Nan) variant mutated in its conserved zinc-finger region and address the mechanism of hypomorphic and neomorphic changes in downstream gene expression. First, we show that Nan-EKLF limits normal EKLF binding to a subset of its sites...
December 20, 2022: Cell Reports
#49
JOURNAL ARTICLE
Xue Qing David Wang, Dandan Fan, Qinyu Han, Yiman Liu, Hongzhi Miao, Xinyu Wang, Qinglan Li, Dong Chen, Haley Gore, Pamela Himadewi, Gerd P Pfeifer, Tomasz Cierpicki, Jolanta Grembecka, Jianzhong Su, Shasha Chong, Liling Wan, Xiaotian Zhang
Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression lead to leukemogenic transformation. Here, for the first time, we comprehensively prove NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes - HOXA/B cluster genes and MEIS1...
December 1, 2022: Cancer Discovery
#50
JOURNAL ARTICLE
Shan Wang, Xiaofang Huo, Yiping Yang, Yingxi Mo, Rahul K Kollipara, Ralf Kittler
The neomorphic transcription factor EWS-FLI1 is a key driver of Ewing sarcoma. Ablation of EWS-FLI1 may present a promising therapeutic strategy for this malignancy. Here we found that the deubiquitinase, ubiquitin specific peptidase 9 X-linked (USP9X) stabilizes EWS-FLI1 protein expression in Ewing sarcoma. We show that USP9X binds the ETS domain of EWS-FLI1 in Ewing sarcoma cells and deubiquitinates EWS-FLI1 and that USP9X and EWS-FLI1 protein expression is correlated in clinical Ewing sarcoma specimens. We found that treatment of Ewing sarcoma cells with the USP9X inhibitor WP1130 mediates rapid EWS-FLI1 degradation in vitro and in vivo which coincides with reduced growth of Ewing sarcoma cells and tumors...
October 29, 2022: Cancer Letters
#51
JOURNAL ARTICLE
Laura Castilla-Vallmanya, Mónica Centeno-Pla, Mercedes Serrano, Héctor Franco-Valls, Raúl Martínez-Cabrera, Aina Prat-Planas, Elena Rojano, Juan A G Ranea, Pedro Seoane, Clara Oliva, Abraham J Paredes-Fuentes, Gemma Marfany, Rafael Artuch, Daniel Grinberg, Raquel Rabionet, Susanna Balcells, Roser Urreizti
BACKGROUND: Schaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2 , mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterisation of SYS pathophysiology at clinical, genetic and molecular levels. METHODS: We performed an extensive phenotypic and mutational revision of previously reported patients with SYS...
September 7, 2022: Journal of Medical Genetics
#52
JOURNAL ARTICLE
Tilman L B Hölting, Florencia Cidre-Aranaz, Dana Matzek, Bastian Popper, Severin J Jacobi, Cornelius M Funk, Florian H Geyer, Jing Li, Ignazio Piseddu, Bruno L Cadilha, Stephan Ledderose, Jennifer Zwilling, Shunya Ohmura, David Anz, Annette Künkele, Frederick Klauschen, Thomas G P Grünewald, Maximilian M L Knott
Chimeric fusion transcription factors are oncogenic hallmarks of several devastating cancer entities including pediatric sarcomas, such as Ewing sarcoma (EwS) and alveolar rhabdomyosarcoma (ARMS). Despite their exquisite specificity, these driver oncogenes have been considered largely undruggable due to their lack of enzymatic activity.Here, we show in the EwS model that - capitalizing on neomorphic DNA-binding preferences - the addiction to the respective fusion transcription factor EWSR1-FLI1 can be leveraged to express therapeutic genes...
October 13, 2022: Molecular Cancer
#53
JOURNAL ARTICLE
Theodore T Nguyen, Flaviane N Silva, Erica A Golemis
The Aurora kinases (AURKA and AURKB) have attracted attention as therapeutic targets in head and neck squamous cell carcinomas. Aurora kinases were first defined as regulators of mitosis that localization to the centrosome (AURKA) and centromere (AURKB), governing formation of the mitotic spindle, chromatin condensation, activation of the core mitotic kinase CDK1, alignment of chromosomes at metaphase, and other processes. Subsequently, additional roles for Aurora kinases have been defined in other phases of cell cycle, including regulation of ciliary disassembly and DNA replication...
September 2022: Cancer Journal
#54
JOURNAL ARTICLE
Alla V Tsytsykova, Graham Wiley, Chuang Li, Richard C Pelikan, Lori Garman, Francis A Acquah, Blaine H M Mooers, Erdyni N Tsitsikov, Ian F Dunn
Krüppel-like factor 4 (KLF4) is a transcription factor that has been proven necessary for both induction and maintenance of pluripotency and self-renewal. Whole-genome sequencing defined a unique mutation in KLF4 (KLF4K409Q ) in human meningiomas. However, the molecular mechanism of this tumor-specific KLF4 mutation is unknown. Using genome-wide high-throughput and focused quantitative transcriptional approaches in human cell lines, primary meningeal cells, and meningioma tumor tissue, we found that a change in the evolutionarily conserved DNA-binding domain of KLF4 alters its DNA recognition preference, resulting in a shift in downstream transcriptional activity...
August 19, 2022: IScience
#55
JOURNAL ARTICLE
Meimei Wang, Zhenyu Yang, Yang Song, Pengfei Wei, Nestor Ishiwme, Liansheng Wang, Hao Zhang, Manman Jing, Meng Gao, Longping Wen, Yunjiao Zhang
Close to half of human cancers harbor point mutations in the tumor-suppressor p53 gene, giving rise to the cellular accumulation of mutant p53 (mutp53) proteins with novel neomorphic gain-of-function (GOF) properties. The destruction of mutp53 proteins through either autophagic or proteasomal degradation is a viable strategy for the targeted therapy of p53-mutated cancers. Several nanomaterials, including zinc-iron and ZIF-8 nanoparticles (NPs), have been reported to induce the proteasomal degradation of mutp53 proteins...
August 2, 2022: Acta Biomaterialia
#56
JOURNAL ARTICLE
Valérie Weber, Lucie Arnaud, Sladjana Dukic-Stefanovic, Barbara Wenzel, Valérie Roux, Jean-Michel Chezal, Thu-Hang Lai, Rodrigo Teodoro, Klaus Kopka, Elisabeth Miot-Noirault, Winnie Deuther-Conrad, Aurélie Maisonial-Besset
Isocitrate dehydrogenases (IDHs) are metabolic enzymes commonly mutated in human cancers (glioma, acute myeloid leukaemia, chondrosarcoma, and intrahepatic cholangiocarcinoma). These mutated variants of IDH (mIDH) acquire a neomorphic activity, namely, conversion of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate involved in tumourigenesis. Thus, mIDHs have emerged as highly promising therapeutic targets, and several mIDH specific inhibitors have been developed. However, the evaluation of mIDH status, currently performed by biopsy, is essential for patient stratification and thus treatment and follow-up...
June 11, 2022: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
#57
JOURNAL ARTICLE
Xiulei Mo, Qiankun Niu, Andrey A Ivanov, Yiu Huen Tsang, Cong Tang, Changfa Shu, Qianjin Li, Kun Qian, Alafate Wahafu, Sean P Doyle, Danielle Cicka, Xuan Yang, Dacheng Fan, Matthew A Reyna, Lee A D Cooper, Carlos S Moreno, Wei Zhou, Taofeek K Owonikoko, Sagar Lonial, Fadlo R Khuri, Yuhong Du, Suresh S Ramalingam, Gordon B Mills, Haian Fu
Comprehensive sequencing of patient tumors reveals genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells...
May 26, 2022: Cell
#58
JOURNAL ARTICLE
Hong Joo Kim, Payam Mohassel, Sandra Donkervoort, Lin Guo, Kevin O'Donovan, Maura Coughlin, Xaviere Lornage, Nicola Foulds, Simon R Hammans, A Reghan Foley, Charlotte M Fare, Alice F Ford, Masashi Ogasawara, Aki Sato, Aritoshi Iida, Pinki Munot, Gautam Ambegaonkar, Rahul Phadke, Dominic G O'Donovan, Rebecca Buchert, Mona Grimmel, Ana Töpf, Irina T Zaharieva, Lauren Brady, Ying Hu, Thomas E Lloyd, Andrea Klein, Maja Steinlin, Alice Kuster, Sandra Mercier, Pascale Marcorelles, Yann Péréon, Emmanuelle Fleurence, Adnan Manzur, Sarah Ennis, Rosanna Upstill-Goddard, Luca Bello, Cinzia Bertolin, Elena Pegoraro, Leonardo Salviati, Courtney E French, Andriy Shatillo, F Lucy Raymond, Tobias B Haack, Susana Quijano-Roy, Johann Böhm, Isabelle Nelson, Tanya Stojkovic, Teresinha Evangelista, Volker Straub, Norma B Romero, Jocelyn Laporte, Francesco Muntoni, Ichizo Nishino, Mark A Tarnopolsky, James Shorter, Carsten G Bönnemann, J Paul Taylor
Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence...
April 28, 2022: Nature Communications
#59
JOURNAL ARTICLE
Chunhui Huang, Christian Fischer, Michelle R Machacek, Stephane Bogen, Tesfaye Biftu, Xianhai Huang, Michael H Reutershan, Ryan Otte, Qingmei Hong, Zhicai Wu, Yang Yu, Min Park, Lei Chen, Purakkattle Biju, Ian Knemeyer, Ping Lu, Christopher J Kochansky, Michael Brendan Hicks, Yong Liu, Roy Helmy, Xavier Fradera, Anthony Donofrio, Josh Close, Matthew L Maddess, Catherine White, David L Sloman, Nunzio Sciammetta, Jun Lu, Craig Gibeau, Vladimir Simov, Hongjun Zhang, Peter Fuller, David Witter
Mutant isocitrate dehydrogenase 1 (IDH1) has been identified as an attractive oncology target for which >70% of grade II and III gliomas and ∼10% of acute myeloid leukemia (AML) harbor somatic IDH1 mutations. These mutations confer a neomorphic gain of function, leading to the production of the oncometabolite ( R )-2-hydroxyglutarate (2-HG). We identified and developed a potent, selective, and orally bioavailable brain-penetrant tricyclic diazepine scaffold that inhibits mutant IDH1. During the course of in vitro metabolism studies, GSH-adduct metabolites were observed...
April 14, 2022: ACS Medicinal Chemistry Letters
#60
JOURNAL ARTICLE
Ouyang Yuan, Amol Ugale, Tommaso de Marchi, Vimala Anthonydhason, Anna Konturek-Ciesla, Haixia Wan, Mohamed Eldeeb, Caroline Drabe, Maria Jassinskaja, Jenny Hansson, Isabel Hidalgo, Talia Velasco-Hernandez, Jörg Cammenga, Jeffrey A Magee, Emma Niméus, David Bryder
Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event...
April 22, 2022: Science Advances
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