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Min Huang, Li Zhu, Jacqueline S Garcia, Michael X Li, Andrew J Gentles, Beverly S Mitchell
We have recently reported that activation of Brd4 is associated with the presence of autophagy in NPMc+ and MLL AML cells. In order to determine the mechanisms underlying this relationship, we have examined the role of Brd4 in regulating the expression of several genes that are central to the process of autophagy. We found that Brd4 binds to the promoters of ATG 3, 7 and CEBPβ, and expression of these genes is markedly reduced by inhibitors of Brd4, as well as by Brd4-shRNA and depletion of CEBPβ. Inhibitors of Brd4 also dramatically suppress the transcription of Keap1, thereby increasing the expression of anti-oxidant genes through the Nrf2 pathway and reducing the cytotoxicity induced by Brd4 inhibitors...
February 20, 2018: Oncotarget
Hyangju Kang, Youngmin Park, Yongjik Lee, Yun-Joo Yoo, Inhwan Hwang
Plants represent promising systems for producing various recombinant proteins. One key area of focus for improving this technology is developing methods for producing recombinant proteins at high levels. Many methods have been developed to increase the transcript levels of recombinant genes. However, methods for increasing protein production involving steps downstream of transcription, including translation, have not been fully explored. Here, we investigated the effects of N-glycosylation on protein production and provide evidence that N-glycosylation greatly increases the expression levels of ER-targeted recombinant proteins...
March 15, 2018: Scientific Reports
Keigo Tsushida, Katsuyuki Tanabe, Kana Masuda, Satoshi Tanimura, Hiromasa Miyake, Yuka Arata, Hitoshi Sugiyama, Jun Wada
Acute kidney injury (AKI) has been associated with not only higher in-hospital mortality but also the subsequent development of chronic kidney disease (CKD). Recent evidence has suggested the involvement of mitochondrial dysfunction and impaired dynamics in the pathogenesis of AKI. Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that acts as a transcription factor to regulate the transcription of genes required for mitochondrial biogenesis and oxidative phosphorylation. In the present study, we examined the effects of ERRα deficiency on the progression of AKI induced by cisplatin...
March 12, 2018: Biochemical and Biophysical Research Communications
Joanna Przybyl, Lukasz Kidzinski, Trevor Hastie, Maria Debiec-Rychter, Roel Nusse, Matt van de Rijn
OBJECTIVE: Low-grade endometrial stromal sarcomas (LGESS) harbor chromosomal translocations that affect proteins associated with chromatin remodeling Polycomb Repressive Complex 2 (PRC2), including SUZ12, PHF1 and EPC1. Roughly half of LGESS also demonstrate nuclear accumulation of β-catenin, which is a hallmark of Wnt signaling activation. However, the targets affected by the fusion proteins and the role of Wnt signaling in the pathogenesis of these tumors remain largely unknown. METHODS: Here we report the results of a meta-analysis of three independent gene expression profiling studies on LGESS and immunohistochemical evaluation of nuclear expression of β-catenin and Lef1 in 112 uterine sarcoma specimens obtained from 20 LGESS and 89 LMS patients...
March 12, 2018: Gynecologic Oncology
Simone B S P Terra, Scott W Aesif, Joseph J Maleszewski, Andrew L Folpe, Jennifer M Boland
Synovial sarcoma (SS), a translocation-associated sarcoma characterized by SS18-SSX1/2 fusion, presents most often in the extremities of young adults. While SS regularly occurs in the pleuropulmonary parenchyma, the mediastinum is an exceedingly rare primary site; the literature on this subject is predominantly composed of case reports and small series, mostly without molecular confirmation. Cases of mediastinal SS were selected from our institutional and consultation archives. Diagnoses were confirmed by either SS18 fluorescence in situ hybridization (n=6) or reverse transcription polymerase chain reaction for SS18-SSX1/2 (n=15)...
March 14, 2018: American Journal of Surgical Pathology
Erina Tonouchi, Yasuyuki Gen, Tomoki Muramatsu, Hidekazu Hiramoto, Kousuke Tanimoto, Jun Inoue, Johji Inazawa
Bromodomain Containing 4 (BRD4) mediates transcriptional elongation of the oncogene MYC by binding to acetylated histones. BRD4 has been shown to play a critical role in tumorigenesis in several cancers, and the BRD4-NUT fusion gene is a driver of NUT midline carcinoma (NMC), a rare but highly lethal cancer. microRNAs (miRNAs) are endogenous small non-coding RNAs that suppress target gene expression by binding to complementary mRNA sequences. Here, we show that miR-3140, which was identified as a novel tumor suppressive miRNA by function-based screening of a library containing 1090 miRNA mimics, directly suppressed BRD4 by binding to its coding sequence (CDS)...
March 14, 2018: Scientific Reports
Hong Zhang, Lin He, Lei Cai
RNA sequencing (RNA-seq) can not only be used to identify the expression of common or rare transcripts but also in the identification of other abnormal events, such as alternative splicing, novel transcripts, and fusion genes. In principle, RNA-seq can be carried out by almost all of the next-generation sequencing (NGS) platforms, but the libraries of different platforms are not exactly the same; each platform has its own kit to meet the special requirements of the instrument design.
2018: Methods in Molecular Biology
Benjamin A Farber, Gadi Lalazar, Elana P Simon, William J Hammond, David Requena, Umesh K Bhanot, Michael P La Quaglia, Sanford M Simon
Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary liver cancer found in adolescents and young adults without underlying liver disease. A deletion of ~400 kD has been found in one copy of chromosome 19 in the tumor tissue of all patients tested. This produces a fusion of the genes DNAJB1 and PRKACA which, in turn, produces a chimeric transcript and protein. Transcriptomic analysis of the tumor has shown upregulation of various oncologically relevant pathways, including EGF/ErbB, Aurora Kinase A, pak21 and wnt...
February 13, 2018: Oncotarget
Diego Hojsgaard
Polyploid genomes evolve and follow a series of dynamic transfigurations along with adaptation and speciation. The initial formation of a new polyploid individual within a diploid population usually involves a triploid bridge, a two-step mechanism of cell fusions between ubiquitous (reduced) and rare (unreduced) gametes. The primary fusion event creates an intermediate triploid individual with unbalanced genome sets, a situation of genomic-shock characterized by gene expression dysregulation, high dosage sensitivity, disturbed cell divisions, and physiological and reproductive attributes drastically altered...
2018: Frontiers in Plant Science
Peiye Shen, Ying Jing, Ruiyun Zhang, Mei-Chun Cai, Pengfei Ma, Haige Chen, Guanglei Zhuang
Neuroendocrine bladder cancer is a relatively rare but often lethal malignancy, with cell of origin, oncogenomic architecture and standard treatment poorly defined. Here we performed comprehensive whole-genome and transcriptome sequencing on a unique cohort of genitourinary neuroendocrine neoplasms, mainly small cell carcinomas of the urinary bladder. The mutational landscape and signatures of neuroendocrine bladder cancer strikingly resembled those in conventional urothelial carcinoma, along with typically mixed histologies, supporting a common cellular origin...
March 14, 2018: Oncogene
Yakai Song, Linjuan Li, Yantao Chen, Jingqiu Liu, Senhao Xiao, Fulin Lian, Naixia Zhang, Hong Ding, Yuanyuan Zhang, Kaixian Chen, Hualiang Jiang, Chenhua Zhang, Yu-Chih Liu, Shijie Chen, Cheng Luo
DOT1L (the disruptor of telomeric silencing 1-like), through its methyltransferase activity of H3K79, plays essential roles in transcriptional regulation, cell cycle regulation, and DNA damage response. In addition, DOT1L is believed to be involved in the development of MLL-rearranged leukemia driven by the MLL (mixed-lineage leukemia) fusion proteins, which thus to be a crucial target for leukemia therapy. Hence, discovering of novel DOT1L inhibitors has been in a great demand. In this study, we initiated the discovering process from setting up the AlphaLISA based High Throughput Screening (HTS) assay of DOT1L...
February 24, 2018: Bioorganic & Medicinal Chemistry
Xiubao Chang, Yuexian Hou
Genome editing is a powerful tool to modify a specific gene and to correct a disease-causing mutation. Recently developed new techniques, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9), significantly facilitate the progression in this field. However, mutations associated with the double strand DNA breaks (DSBs) introduced by these systems hampered their direct usage in clinic. In order to prevent the mutations caused by DSBs, we have designed a novel mean to induce homology-directed recombination (HDR) without DSBs, i...
2018: International Journal of Biochemistry and Molecular Biology
Summer J Rozzi, Valeria Avdoshina, Jerel A Fields, Italo Mocchetti
Human immunodeficiency virus-1 (HIV) infection of the central nervous system promotes neuronal injury that culminates in HIV-associated neurocognitive disorders. Viral proteins, including transactivator of transcription (Tat), have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear. Tat transgenic mice or neurons exposed to Tat, which show neuronal loss, exhibit smaller mitochondria as compared to controls. To provide an experimental clue as to which mechanisms are used by Tat to promote changes in mitochondrial morphology, rat cortical neurons were exposed to Tat (100 nM) for various time points...
December 2018: Cell Death Discovery
Barbara J McClure, Susan L Heatley, Chung H Kok, Teresa Sadras, Jiyuan An, Timothy P Hughes, Richard B Lock, David Yeung, Rosemary Sutton, Deborah L White
BACKGROUND: Zinc-finger protein 384 (ZNF384) fusions are an emerging subtype of precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL) and here we further characterised their prevalence, survival outcomes and transcriptome. METHODS: Bone marrow mononuclear cells from 274 BCR-ABL1-negative pre-B-ALL patients were immunophenotyped and transcriptome molecularly characterised. Transcriptomic data was analysed by principal component analysis and gene-set enrichment analysis to identify gene and pathway expression changes...
March 13, 2018: British Journal of Cancer
Christine M Hustmyer, Chelsea A Simpson, Stephen G Olney, Matthew L Bochman, Julia C van Kessel
Experimental studies of transcriptional regulation in bacteria require the ability to precisely measure changes in gene expression, often accomplished through the use of reporter genes. However, the boundaries of promoter sequences required for transcription are often unknown, thus complicating construction of reporters and genetic analysis of transcriptional regulation. Here, we analyze reporter libraries to define the promoter boundaries of the luxCDABE bioluminescence operon and the betIBA-proXWV osmotic stress operon in Vibrio harveyi We describe a new method called RAIL (<u>R</u>apid<u>A</u>rbitrary PCR<u>I</u>nsertion<u>L</u>ibraries) that combines the power of arbitrary PCR and isothermal DNA assembly to rapidly clone promoter fragments of various lengths upstream of reporter genes to generate large libraries...
March 12, 2018: Journal of Bacteriology
Stephanie M Prezioso, Kevin Xue, Nelly Leung, Scott D Gray-Owen, Dinesh Christendat
Listeria monocytogenes is a common food-borne bacterial pathogen that contaminates plant and animal consumable products. The persistent nature of L. monocytogenes is associated with millions of food recalls annually. Here, we describe the role of shikimate in directly modulating the expression of genes encoding enzymes for the conversion of quinate and shikimate metabolites to protocatechuate. In L. monocytogenes these genes are found within two operons, named qui1 and qui2. Additionally, a gene named quiR, encoding a LysR-Type Transcriptional Regulator (QuiR), is located immediately upstream of the qui1 operon...
March 9, 2018: Journal of Molecular Biology
Maciej Dylewski, Monika Ćwiklińska, Katarzyna Potrykus
Small RNA are very important post-transcriptional regulators in both, bacteria and eukaryotes. One of such sRNA is GraL, encoded in the greA leader region and conserved among enteric bacteria. Here, we conducted a bioinformatics search for GraL's targets in trans and validated our findings in vivo by constructing fusions of probable targets with lacZ and measuring their activity when GraL was overexpressed. Only one target's activity (nudE) decreased under those conditions and was thus selected for further analysis...
March 12, 2018: Acta Biochimica Polonica
Khadega A Abuelgasim, Hinna Rehan, Maha Alsubaie, Nasser Al Atwi, Mohammed Al Balwi, Saeed Alshieban, Areej Almughairi
BACKGROUND: Chronic lymphocytic leukemia and chronic myeloid leukemia are the most common types of adult leukemia. However, it is rare for the same patient to suffer from both. Richter's transformation to diffuse large B-cell lymphoma is frequently observed in chronic lymphocytic leukemia. Purine analog therapy and the presence of trisomy 12, and CCND1 gene rearrangement have been linked to increased risk of Richter's transformation. The coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma in the same patient is extremely rare, with only nine reported cases...
March 11, 2018: Journal of Medical Case Reports
Francesca Martorana, Daniela Gaglio, Maria Rosaria Bianco, Federica Aprea, Assunta Virtuoso, Marcella Bonanomi, Lilia Alberghina, Michele Papa, Anna Maria Colangelo
Neuronal differentiation involves extensive modification of biochemical and morphological properties to meet novel functional requirements. Reorganization of the mitochondrial network to match the higher energy demand plays a pivotal role in this process. Mechanisms of neuronal differentiation in response to nerve growth factor (NGF) have been largely characterized in terms of signaling, however, little is known about its impact on mitochondrial remodeling and metabolic function. In this work, we show that NGF-induced differentiation requires the activation of autophagy mediated by Atg9b and Ambra1, as it is disrupted by their genetic knockdown and by autophagy blockers...
March 9, 2018: Cell Death & Disease
Katrin Schelleckes, Boris Schmitz, Malte Lenders, Mirja Mewes, Stefan-Martin Brand, Eva Brand
KIBRA has been suggested as a key regulator of the hippo pathway, regulating organ size, cell contact inhibition as well as tissue regeneration and tumorigenesis. Recently, alterations of KIBRA expression caused by promotor methylation have been reported for several types of cancer. Our current study aimed to design an artificial transcription factor capable of re-activating expression of the tumor suppressor KIBRA and the hippo pathway. We engineered a new gene named 'ZFP226' encoding for a ~23 kDa fusion protein...
March 9, 2018: Scientific Reports
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