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Regulated Alternative Translocation

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https://www.readbyqxmd.com/read/28628091/the-btg2-prmt1-module-limits-pre-b-cell-expansion-by-regulating-the-cdk4-cyclin-d3-complex
#1
Elmar Dolezal, Simona Infantino, Friedel Drepper, Theresa Börsig, Aparajita Singh, Thomas Wossning, Gina J Fiala, Susana Minguet, Bettina Warscheid, David M Tarlinton, Hassan Jumaa, David Medgyesi, Michael Reth
Developing pre-B cells in the bone marrow alternate between proliferation and differentiation phases. We found that protein arginine methyl transferase 1 (PRMT1) and B cell translocation gene 2 (BTG2) are critical components of the pre-B cell differentiation program. The BTG2-PRMT1 module induced a cell-cycle arrest of pre-B cells that was accompanied by re-expression of Rag1 and Rag2 and the onset of immunoglobulin light chain gene rearrangements. We found that PRMT1 methylated cyclin-dependent kinase 4 (CDK4), thereby preventing the formation of a CDK4-Cyclin-D3 complex and cell cycle progression...
June 19, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28608501/targeting-hypoxia-mediated-yap1-nuclear-translocation-ameliorates-pathogenesis-of-endometriosis-without-compromising-maternal-fertility
#2
Shih-Chieh Lin, Hsiu-Chi Lee, Pei-Chi Hou, Jhao-Lin Fu, Meng-Hsing Wu, Shaw-Jenq Tsai
Endometriosis is a highly prevalent gynecological disease that severely reduces women's health and quality of life. Ectopic endometriotic lesions have evolved mechanisms to survive in the hypoxic peritoneal microenvironment by regulating the expression of a significant subset of genes. However, the master regulator controlling these genes remains to be characterized. Herein, by using bioinformatics analysis and experimental verification, we identified Yes-Associated Protein 1 (YAP1) as a master regulator of endometriosis...
June 12, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28584094/reconstructing-blood-stem-cell-regulatory-network-models-from-single-cell-molecular-profiles
#3
Fiona K Hamey, Sonia Nestorowa, Sarah J Kinston, David G Kent, Nicola K Wilson, Berthold Göttgens
Adult blood contains a mixture of mature cell types, each with specialized functions. Single hematopoietic stem cells (HSCs) have been functionally shown to generate all mature cell types for the lifetime of the organism. Differentiation of HSCs toward alternative lineages must be balanced at the population level by the fate decisions made by individual cells. Transcription factors play a key role in regulating these decisions and operate within organized regulatory programs that can be modeled as transcriptional regulatory networks...
June 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28578400/lipid-droplet-associated-hydrolase-promotes-lipid-droplet-fusion-and-enhances-atgl-degradation-and-triglyceride-accumulation
#4
Young-Hwa Goo, Se-Hee Son, Antoni Paul
Lipid droplet (LD)-associated hydrolase (LDAH) is a newly identified LD protein abundantly expressed in tissues that predominantly store triacylglycerol (TAG). However, how LDAH regulates TAG metabolism remains unknown. We found that upon oleic acid loading LDAH translocalizes from the ER to newly formed LDs, and induces LD coalescence in a tubulin-dependent manner. LDAH overexpression and downregulation in HEK293 cells increase and decrease, respectively, TAG levels. Pulse and chase experiments show that LDAH enhances TAG biogenesis, but also decreases TAG turnover and fatty acid release from cells...
June 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28557017/novel-compounds-targeting-the-enterohaemorrhagic-escherichia-coli-type-three-secretion-system-reveal-insights-into-mechanisms-of-secretion-inhibition
#5
Riccardo Zambelloni, James P R Connolly, Alejandro Huerta Uribe, Karl Burgess, Rodolfo Marquez, Andrew J Roe
Anti-virulence (AV) compounds are a promising alternative to traditional antibiotics for fighting bacterial infections. The Type Three Secretion System (T3SS) is a well-studied and attractive AV target, given that it is widespread in more than 25 species of Gram-negative bacteria, including enterohaemorrhagic E. coli (EHEC), and since it is essential for host colonisation by many pathogens. In this work, we designed, synthesized and tested a new series of compounds that block the functionality of the T3SS of EHEC...
May 29, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28556300/development-of-protein-degradation-inducers-of-oncogenic-bcr-abl-protein-by-conjugation-of-abl-kinase-inhibitors-and-iap-ligands
#6
Norihito Shibata, Naoki Miyamoto, Katsunori Nagai, Kenichiro Shimokawa, Tomoya Sameshima, Nobumichi Ohoka, Takayuki Hattori, Yasuhiro Imaeda, Hiroshi Nara, Nobuo Cho, Mikihiko Naito
Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase such as imatinib and dasatinib exhibit remarkable therapeutic effects, though emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to down-regulate the BCR-ABL protein. We have devised a protein knockdown system by hybrid molecules named SNIPERs (Specific and Non-genetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers), which is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR-ABL protein has been developed recently...
May 26, 2017: Cancer Science
https://www.readbyqxmd.com/read/28543886/human-hairless-protein-roles-in-skin-hair-and-emerging-connections-to-brain-and-other-cancers
#7
Anas Maatough, G Kerr Whitfield, Lemlem Brook, David Hsieh, Patricia Palade, Jui-Cheng Hsieh
The mammalian hairless protein (HR) is a 130 kDa nuclear transcription factor that is essential for proper skin and hair follicle function. Previous studies have focused on the role of HR in skin maintenance and hair cycling. However, hairless gene (HR) is also expressed in brain and other tissues, where its role remains poorly understood. HR has been reported to contain functional domains that potentially serve in DNA binding, histone demethylation, nuclear translocation signal, and protein-protein interactions...
May 23, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28513634/mitochondria-targeted-platinum-ii-complexes-dual-inhibitory-activities-on-tumor-cell-proliferation-and-migration-invasion-via-intracellular-trafficking-of-%C3%AE-catenin
#8
Jingling Li, Xiaoli He, Yeling Zou, Dandan Chen, Liecheng Yang, Jiaming Rao, Huabing Chen, Michael C W Chan, Lin Li, Zhengqing Guo, Leshuai W Zhang, Chunying Chen
Mitochondria-targeted therapy is an alternative strategy for cancer therapy and may overcome the problems of metastasis and drug resistance that usually occur in conventional treatment. In this work, we demonstrate the mitochondria-targeted delivery of a cationic cyclometalated platinum(ii) complex, PIP-platin, in cancer cells. PIP-platin showed selective delivery and accumulation in the mitochondria and exhibited toxicity against a variety of tumor cell lines. The mitochondria were disrupted by PIP-platin, along with the generation of reactive oxygen species, depolarization of mitochondrial membrane potential, release of cytochrome c and necrosis...
June 21, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28512350/mechanisms-of-action-and-regulation-of-atp-dependent-chromatin-remodelling-complexes
#9
REVIEW
Cedric R Clapier, Janet Iwasa, Bradley R Cairns, Craig L Peterson
Cells utilize diverse ATP-dependent nucleosome-remodelling complexes to carry out histone sliding, ejection or the incorporation of histone variants, suggesting that different mechanisms of action are used by the various chromatin-remodelling complex subfamilies. However, all chromatin-remodelling complex subfamilies contain an ATPase-translocase 'motor' that translocates DNA from a common location within the nucleosome. In this Review, we discuss (and illustrate with animations) an alternative, unifying mechanism of chromatin remodelling, which is based on the regulation of DNA translocation...
July 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28503306/the-drive-to-generate-multiple-forms-of-oncogenic-cyclin-d1-transcripts-in-mantle-cell-lymphoma
#10
EDITORIAL
Chioniso Patience Masamha
Alternative polyadenylation is a rapidly emerging form of gene regulation, which in its simplest form, enables the generation of mRNA transcripts that code for the same protein but have 3'UTRs of different lengths and regulatory content. For oncogenes, shorter 3'UTRs would be preferred as a mechanism to evade miRNA regulation. The shortening of the 3'UTR of cyclin D1 in mantle cell lymphoma offers provocative insights into this process. Patient samples have revealed that 3'UTR shortening may occur due to mutations, or translocations that result in the generation of a chimeric 3'UTR...
2017: Biomarker Research
https://www.readbyqxmd.com/read/28467182/roles-of-silent-information-regulator-1-serine-arginine-rich-splicing-factor-10-lipin-1-axis-in-the-pathogenesis-of-alcohol-fatty-liver-disease
#11
Yuanyuan Li, Junying Zhou
Alcohol exposure is a major reason of morbidity and mortality all over the world, with much of detrimental consequences attributing to alcoholic liver disease (ALD). With the continued ethanol consumption, alcoholic fatty liver disease (AFLD, the earliest and reversible form of ALD) can further develop to more serious forms of alcoholic liver damage, including alcoholic steatohepatitis, fibrosis/cirrhosis, and even eventually progress to hepatocellular carcinoma and liver failure. Furthermore, cell trauma, inflammation, oxidative stress, regeneration, and bacterial translocation are crucial promoters of ethanol-mediated liver lesions...
June 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28465491/discovery-and-characterization-of-small-molecules-targeting-the-dna-binding-ets-domain-of-erg-in-prostate-cancer
#12
Miriam S Butler, Mani Roshan-Moniri, Michael Hsing, Desmond Lau, Ari Kim, Paul Yen, Marta Mroczek, Mannan Nouri, Scott Lien, Peter Axerio-Cilies, Kush Dalal, Clement Yau, Fariba Ghaidi, Yubin Guo, Takeshi Yamazaki, Sam Lawn, Martin E Gleave, Cheryl Y Gregory-Evans, Lawrence P McIntosh, Michael E Cox, Paul S Rennie, Artem Cherkasov
Genomic alterations involving translocations of the ETS-related gene ERG occur in approximately half of prostate cancer cases. These alterations result in aberrant, androgen-regulated production of ERG protein variants that directly contribute to disease development and progression. This study describes the discovery and characterization of a new class of small molecule ERG antagonists identified through rational in silico methods. These antagonists are designed to sterically block DNA binding by the ETS domain of ERG and thereby disrupt transcriptional activity...
April 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28447783/real-time-detection-reveals-responsive-cotranscriptional-formation-of-persistent-intramolecular-dna-and-intermolecular-dna-rna-hybrid-g-quadruplexes-stabilized-by-r-loop
#13
Yang Zhao, Jia-Yu Zhang, Zong-Yu Zhang, Tan-Jun Tong, Yu-Hua Hao, Zheng Tan
G-quadruplex (GQ) structures are implicated in important physiological and pathological processes. Millions of GQ-forming motifs are enriched near transcription start sites (TSSs) of animal genes. Transcription can induce the formation of GQs, which in turn regulate transcription. The kinetics of the formation and persistence of GQs in transcription is crucial for the role they play but has not yet been explored. We established a method based on the fluorescence resonance energy transfer (FRET) technique to monitor in real-time the cotranscriptional formation and post-transcriptional persistence of GQs in DNA...
June 6, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28408318/regulation-of-agr2-expression-via-3-utr-shortening
#14
Eva Matoulkova, Lucia Sommerova, Michal Pastorek, Borivoj Vojtesek, Roman Hrstka
One recently discussed general mechanism affecting gene expression is 3'-untranslated region (3'UTR) length. Events such as shortening, translocation or loss of 3'UTRs are observed within oncogenes and are proposed to associate with increased expression. Thus, increased efforts are being made to understand constitutive and differential transcript 3'end formation. Investigation of AGR2 mRNA revealed a direct impact of its 3'UTR length on AGR2 expression. In silico analyses identified several regulatory sequences within the distal part of AGR2 mRNA that may regulate 3'UTR length and associated protein levels...
April 11, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28349780/ganoderic-acid-targeting-nuclear-factor-erythroid-2-related-factor-2-in-lung-cancer
#15
Balraj Singh Gill, Sanjeev Kumar, Navgeet
Lung cancer causes huge mortality worldwide, and targeting new pathway may provide an alternative in modulating signaling in cancer. Nuclear factor erythroid 2-related factor 2 is the major regulator of endogenous and exogenous stress by activating numerous antioxidant genes critical in cancer, Alzheimer's, Parkinson's, and inflammatory bowel diseases. Ganoderic acid is a triterpene from basiodiomycetes fungus Ganoderma lucidum with numerous therapeutic effects. In this study, ganoderic acid and its 50 isomers and natural activators were docked by receptor-based molecular docking using Maestro 9...
March 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28340354/mechanism-of-substrate-translocation-in-an-alternating-access-transporter
#16
Naomi R Latorraca, Nathan M Fastman, A J Venkatakrishnan, Wolf B Frommer, Ron O Dror, Liang Feng
Transporters shuttle molecules across cell membranes by alternating among distinct conformational states. Fundamental questions remain about how transporters transition between states and how such structural rearrangements regulate substrate translocation. Here, we capture the translocation process by crystallography and unguided molecular dynamics simulations, providing an atomic-level description of alternating access transport. Simulations of a SWEET-family transporter initiated from an outward-open, glucose-bound structure reported here spontaneously adopt occluded and inward-open conformations...
March 23, 2017: Cell
https://www.readbyqxmd.com/read/28321271/parkin-in-cancer-mitophagy-related-unrelated-tasks
#17
EDITORIAL
Nabil Eid, Yoichi Kondo
Dysfunctional mitochondria may produce excessive reactive oxygen species, thus inducing DNA damage, which may be oncogenic if not repaired. As a major role of the PINK1-Parkin pathway involves selective autophagic clearance of damaged mitochondria via a process termed mitophagy, Parkin-mediated mitophagy may be a tumor-suppressive mechanism. As an alternative mechanism for tumor inhibition beyond mitophagy, Parkin has been reported to have other oncosuppressive functions such as DNA repair, negative regulation of cell proliferation and stimulation of p53 tumor suppressor function...
March 8, 2017: World Journal of Hepatology
https://www.readbyqxmd.com/read/28284859/molecular-mechanisms-of-3-3-4-4-5-pentachlorobiphenyl-induced-epithelial-mesenchymal-transition-in-human-hepatocellular-carcinoma-cells
#18
Li Song, Linlin Guo, Zhuoyu Li
Polychlorinated biphenyls (PCBs) are classic persistent organic pollutants (POPs). Many studies have found a positive association between the progression of hepatocellular carcinoma (HCC) and PCBs exposure. However, the influence of PCBs on epithelial-mesenchymal transition (EMT) of HCC remains to be unclear. In this study, we explored the effect of PCB126 on EMT in HCC cells and its underlying mechanisms. The data showed that PCB126, exposing both Bel-7402 and SMMC-7721 cells for 48h, promoted EMT that was demonstrated by E-cadherin repression, up-regulation of N-cadherin and vimentin, and morphological alteration...
May 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28215533/plastid-protein-targeting-preprotein-recognition-and-translocation
#19
P Chotewutmontri, K Holbrook, B D Bruce
Eukaryotic organisms are defined by their endomembrane system and various organelles. The membranes that define these organelles require complex protein sorting and molecular machines that selectively mediate the import of proteins from the cytosol to their functional location inside the organelle. The plastid possibly represents the most complex system of protein sorting, requiring many different translocons located in the three membranes found in this organelle. Despite having a small genome of its own, the vast majority of plastid-localized proteins is nuclear encoded and must be posttranslationally imported from the cytosol...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28068633/polyphenol-rich-ethanolic-extract-from-boerhavia-diffusa-l-mitigates-angiotensin-ii-induced-cardiac-hypertrophy-and-fibrosis-in-rats
#20
Prathapan A, Mathews V Varghese, Abhilash S, Salin Raj P, Anil K Mathew, Anupama Nair, R Harikumaran Nair, Raghu K G
Boerhavia diffusa is a renowned edible medicinal plant extensively used against different ailments including heart diseases in the traditional system of medicine in several countries. The present study aims to evaluate the therapeutic efficacy of ethanolic extract of Boerhavia diffusa (BDE) on cardiac hypertrophy and fibrosis induced by angiotensin II (Ang II) in male wistar rats and to identify the active components present in it. A substantial increase of hypertrophy markers such as cardiac mass index, concentration of ANP and BNP, cardiac injury markers like CK-MB, LDH and SGOT, has been observed in hypertrophied groups whereas BDE treatment attenuated these changes when compared to hypertrophied rats...
March 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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