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Monica J Lewis, Jianzhong Liu, Emily Falk Libby, Minnkyong Lee, Nigel P S Crawford, Douglas R Hurst
SIN3 corepressor complexes play important roles in both normal development and breast cancer. Mammalian cells have two paralogs of SIN3 (SIN3A and SIN3B) that are encoded by distinct genes and have unique functions in many developmental processes. However, specific roles for SIN3A and SIN3B in breast cancer progression have not been characterized. We generated stable knockdown cells of SIN3 paralogs individually and in combination using three non-overlapping shRNA. Stable knockdown of SIN3B caused a significant decrease in transwell invasion through Matrigel and decreased the number of invasive colonies when grown in a 3D extracellular matrix...
October 21, 2016: Oncotarget
Felix Kliewe, Jacqueline Kumme, Mathias Grigat, Stefan Hintze, Hans-Joachim Schüller
Structural genes of phospholipid biosynthesis in the yeast S. cerevisiae are transcribed when precursor molecules inositol and choline (IC) are limiting. Gene expression is stimulated by the heterodimeric activator Ino2/Ino4 which binds to ICRE (inositol/choline-responsive element) promoter sequences. Activation is prevented by repressor Opi1, counteracting Ino2 when high concentrations of IC are available. Here we show that ICRE-dependent gene activation is not only repressed by an excess of IC but also under conditions of phosphate starvation...
October 15, 2016: Yeast
Piyush Deokar, Monica Vasiliu, David A Dixon, Karl O Christe, Ralf Haiges
The binary zirconium and hafnium polyazides [PPh4 ]2 [M(N3 )6 ] (M=Zr, Hf) were obtained in near quantitative yields from the corresponding metal fluorides MF4 by fluoride-azide exchange reactions with Me3 SiN3 in the presence of two equivalents of [PPh4 ][N3 ]. The novel polyazido compounds were characterized by their vibrational spectra and their X-ray crystal structures. Both anion structures provide experimental evidence for near-linear M-N-N coordination of metal azides. The species [M(N3 )4 ], [M(N3 )5 ](-) and [M(N3 )6 ](2-) (M=Ti, Zr, Hf) were studied by quantum chemical calculations at the electronic structure density functional theory and MP2 levels...
October 13, 2016: Angewandte Chemie
Kaori Terasaki, Sydney I Ramirez, Shinji Makino
Rift Valley fever virus (RVFV), a member of the genus Phlebovirus within the family Bunyaviridae, causes periodic outbreaks in livestocks and humans in countries of the African continent and Middle East. RVFV NSs protein, a nonstructural protein, is a major virulence factor that exhibits several important biological properties. These include suppression of general transcription, inhibition of IFN-β promoter induction and degradation of double-stranded RNA-dependent protein kinase R. Although each of these biological functions of NSs are considered important for countering the antiviral response in the host, the individual contributions of these functions towards RVFV virulence remains unclear...
October 2016: PLoS Neglected Tropical Diseases
D R Welch, C A Manton, D R Hurst
Metastasis requires coordinated expression of multiple genetic cassettes, often via epigenetic regulation of gene transcription. BRMS1 blocks metastasis, but not orthotopic tumor growth in multiple tumor types, presumably via SIN3 chromatin remodeling complexes. Although there is an abundance of strong data supporting BRMS1 as a metastasis suppressor, the mechanistic data directly connecting molecular pathways with inhibition of particular steps in metastasis are not well defined. In this review, the data for BRMS1-mediated metastasis suppression in multiple tumor types are discussed along with the steps in metastasis that are inhibited...
2016: Advances in Cancer Research
Martin Hermus, Aria Mansouri Tehrani, Jakoah Brgoch
A structural instability in the orthorhombic carbonitridosilicate La2Si4N6C arises when calculating the ab initio phonon dispersion curves. The presence of imaginary modes indicates the compound reported in space group Pnma is dynamically unstable with the eigenvectors showing a monoclinic distortion pathway leading to space group P21/c. Synthesizing La2Si4N6C using a high-temperature route and conducting a co-refinement with high-resolution synchrotron X-ray and neutron powder diffraction shows the predicted peak splitting confirming the predicted lower symmetry crystal structure...
September 19, 2016: Inorganic Chemistry
Yeon-Jin Kwon, Boris A Leibovitch, Nidhi Bansal, Lutecia Pereira, Chi-Yeh Chung, Edgardo V Ariztia, Arthur Zelent, Eduardo F Farias, Samuel Waxman
Cancer cell invasion is an obligatory step for metastatic dissemination that contributes to rapid relapse and a poorer survival in triple negative breast cancer (TNBC) patients. Development of novel therapeutic strategies to block tumor invasion is an unmet need in the treatment of cancer. We reported that the selective inhibition of the PAH2 domain of SIN3A protein function markedly suppressed metastatic dissemination to the lungs in TNBC xenograft bearing mice. Here, we show that TNBC cell lines treated with Sin3 interaction domain (SID) decoy peptides that bind to PAH2 display a strong in vitro inhibition of transwell invasion...
August 19, 2016: Oncotarget
Tianyi Zhang, Zhentao Sheng, Wei Du
Inactivation of HDAC1 and its homolog HDAC2 or addition of HDAC inhibitors in mammalian systems induces apoptosis, cell cycle arrest, and developmental defects. Although these phenotypes have been extensively characterized, the precise underlying mechanisms remain unclear, particularly in in vivo settings. In this study, we show that inactivation of Rpd3, the only HDAC1 and HDAC2 ortholog in Drosophila, induced apoptosis and clone elimination in the developing eye and wing imaginal discs. Depletion of Rpd3 by RNAi cell-autonomously increased JNK activities and decreased activities of Yki, the nuclear effecter of Hippo signaling pathway...
August 2016: Mechanisms of Development
Nidhi Bansal, Almudena Bosch, Boris Leibovitch, Lutecia Pereira, Elena Cubedo, Jianshi Yu, Keely Pierzchalski, Jace W Jones, Melissa Fishel, Maureen Kane, Arthur Zelent, Samuel Waxman, Eduardo Farias
Triple negative breast cancer (TNBC) frequently relapses locally, regionally or as systemic metastases. Development of targeted therapy that offers significant survival benefit in TNBC is an unmet clinical need. We have previously reported that blocking interactions between PAH2 domain of chromatin regulator Sin3A and the Sin3 interaction domain (SID) containing proteins by SID decoys result in EMT reversal, and re-expression of genes associated with differentiation. Here we report a novel and therapeutically relevant combinatorial use of SID decoys...
June 7, 2016: Oncotarget
Yanfang Ye, Lucy Kirkham-McCarthy, Robert S Lahue
Trinucleotide repeats (TNRs) are tandem arrays of three nucleotides that can expand in length to cause at least 17 inherited human diseases. Somatic expansions in patients can occur in differentiated tissues where DNA replication is limited and cannot be a primary source of somatic mutation. Instead, mouse models of TNR diseases have shown that both inherited and somatic expansions can be suppressed by the loss of certain DNA repair factors. It is generally believed that these repair factors cause misprocessing of TNRs, leading to expansions...
July 2016: DNA Repair
Ashlesha Chaubal, Sokol V Todi, Lori A Pile
SIN3 is a transcriptional corepressor that acts as a scaffold for a histone deacetylase (HDAC) complex. The SIN3 complex regulates various biological processes, including organ development, cell proliferation, and energy metabolism. Little is known, however, about the regulation of SIN3 itself. There are two major isoforms of Drosophila SIN3, 187 and 220, which are differentially expressed. Intrigued by the developmentally timed exchange of SIN3 isoforms, we examined whether SIN3 187 controls the fate of the 220 counterpart...
May 27, 2016: Journal of Biological Chemistry
N Bansal, G David, E Farias, S Waxman
Revolutionizing treatment strategies is an urgent clinical need in the fight against cancer. Recently the scientific community has recognized chromatin-associated proteins as promising therapeutic candidates. However, there is a need to develop more targeted epigenetic inhibitors with less toxicity. Sin3 family is one such target which consists of evolutionary conserved proteins with two paralogues Sin3A and Sin3B. Sin3A/B are global transcription regulators that provide a versatile platform for diverse chromatin-modifying activities...
2016: Advances in Cancer Research
C S Lyu, Y L Zhang, J H Lang
OBJECTIVE: To investigate the efficiency of biological function of AT rich interaction domain 1A (ARID1A) gene silenced by small interfering RNA (siRNA) on ovarian clear cell carcinoma ES2 cell line. METHODS: (1) The three pairs ARID1A gene siRNA interference fragments siN1 (ARID1A-705), siN2 (ARID1A-1513), siN3 (ARID1A-2282) and one pair negative control were respectively designed, and transfected into ES2 cells by RNA interference max reagent transiently. Reverse transcription (RT)-PCR and western blot methods were used to detect the expression of ARID1A mRNA and protein in ES2 cells transfected with interference fragments respectively...
March 2016: Zhonghua Fu Chan Ke za Zhi
Hua Yang, Xinye Liu, Mingming Xin, Jinkun Du, Zhaorong Hu, HuiRu Peng, Vincenzo Rossi, Qixin Sun, Zhongfu Ni, Yingyin Yao
Histone deacetylases (HDACs) regulate histone acetylation levels by removing the acetyl group from lysine residues. The maize (Zea mays) HDACHDA101 influences several aspects of development, including kernel size; however, the molecular mechanism by which HDA101 affects kernel development remains unknown. In this study, we find that HDA101 regulates the expression of transfer cell-specific genes, suggesting that their misregulation may be associated with the defects in differentiation of endosperm transfer cells and smaller kernels observed in hda101 mutants...
March 2016: Plant Cell
Nirmalya Saha, Mengying Liu, Ambikai Gajan, Lori A Pile
BACKGROUND: The multisubunit SIN3 complex is a global transcriptional regulator. In Drosophila, a single Sin3A gene encodes different isoforms of SIN3, of which SIN3 187 and SIN3 220 are the major isoforms. Previous studies have demonstrated functional non-redundancy of SIN3 isoforms. The role of SIN3 isoforms in regulating distinct biological processes, however, is not well characterized. RESULTS: We established a Drosophila S2 cell culture model system in which cells predominantly express either SIN3 187 or SIN3 220...
2016: BMC Genomics
Ambikai Gajan, Valerie L Barnes, Mengying Liu, Nirmalya Saha, Lori A Pile
BACKGROUND: Regulation of gene expression by histone-modifying enzymes is essential to control cell fate decisions and developmental processes. Two histone-modifying enzymes, RPD3, a deacetylase, and dKDM5/LID, a demethylase, are present in a single complex, coordinated through the SIN3 scaffold protein. While the SIN3 complex has been demonstrated to have functional histone deacetylase activity, the role of the demethylase dKDM5/LID as part of the complex has not been investigated. RESULTS: Here, we analyzed the developmental and transcriptional activities of dKDM5/LID in relation to SIN3...
2016: Epigenetics & Chromatin
Radhika A Varier, Enrique Carrillo de Santa Pau, Petra van der Groep, Rik G H Lindeboom, Filomena Matarese, Anneloes Mensinga, Arne H Smits, Raghu Ram Edupuganti, Marijke P Baltissen, Pascal W T C Jansen, Natalie Ter Hoeve, Danny R van Weely, Ina Poser, Paul J van Diest, Hendrik G Stunnenberg, Michiel Vermeulen
Recent work from others and us revealed interactions between the Sin3/HDAC complex, the H3K4me3 demethylase KDM5A, GATAD1, and EMSY. Here, we characterize the EMSY/KDM5A/SIN3B complex in detail by quantitative interaction proteomics and ChIP-sequencing. We identify a novel substoichiometric interactor of the complex, transcription factor ZNF131, which recruits EMSY to a large number of active, H3K4me3 marked promoters. Interestingly, using an EMSY knock-out line and subsequent rescue experiments, we show that EMSY is in most cases positively correlated with transcriptional activity of its target genes and stimulates cell proliferation...
April 1, 2016: Journal of Biological Chemistry
Ralf Haiges, Juri Skotnitzki, Zongtang Fang, David A Dixon, Karl O Christe
A series of novel molybdenum(V) and tungsten(VI) oxoazides was prepared starting from [MOF4 ] (M=Mo, W) and Me3 SiN3 . While [WO(N3 )4 ] was formed through fluoride-azide exchange in the reaction of Me3 SiN3 with WOF4 in SO2 solution, the reaction with MoOF4 resulted in a reduction of Mo(VI) to Mo(V) and formation of [MoO(N3 )3 ]. Carried out in acetonitrile solution, these reactions resulted in the isolation of the corresponding adducts [MoO(N3 )3 ⋅2 CH3 CN] and [WO(N3 )4 ⋅CH3 CN]. Subsequent reactions of [MoO(N3 )3 ] with 2,2'-bipyridine and [PPh4 ][N3 ] resulted in the formation and isolation of [(bipy)MoO(N3 )3 ] and [PPh4 ]2 [MoO(N3 )5 ], respectively...
December 14, 2015: Angewandte Chemie
Natascia Guida, Giusy Laudati, Serenella Anzilotti, Rossana Sirabella, Ornella Cuomo, Paola Brancaccio, Marianna Santopaolo, Mario Galgani, Paolo Montuori, Gianfranco Di Renzo, Lorella M T Canzoniero, Luigi Formisano
Methylmercury (MeHg) is a highly neurotoxic compound that, in adequate doses, can cause damage to the brain, including developmental defects and in severe cases cell death. The RE-1-silencing transcription factor (REST) has been found to be involved in the neurotoxic effects of environmental pollutants such as polychlorinated biphenyls (PCBs). In this study, we investigated the effects of MeHg treatment on REST expression and its role in MeHg-induced neurotoxicity in neuroblastoma SH-SY5Y cells. We found that MeHg exposure caused a dose- and time- dependent apoptotic cell death, as evidenced by the appearance of apoptotic hallmarks including caspase-3 processing and annexin V uptake...
January 2016: Neurotoxicology
Michael David Clark, Yongbo Zhang, Ishwar Radhakrishnan
The Sds3 transcriptional corepressor facilitates the assembly of the 1- to 2-MDa histone deacetylase-associated Sin3L/Rpd3L complex by providing a crucial homodimerization activity. Sds3 engages the scaffolding protein Sin3A, via a bipartite motif within the Sin3 interaction domain (SID) comprising a helix and an extended segment. Here, we show that the SID samples two discrete, substantially populated conformations with lifetimes in the tens of milliseconds range. The two conformations differ via a translation of the main chain and the corresponding side chains in the 5- to 7-Å range...
December 4, 2015: Journal of Molecular Biology
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