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Fish L, Pencheva N, Goodarzi H, Tran H, Yoshida M, Tavazoie SF
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Muscleblind-like 1 suppresses breast cancer metastatic colonization and stabilizes metastasis suppressor transcripts
GENES & DEVELOPMENT 2016 FEB 15; 30(4):386-398
Post-transcriptional deregulation is a defining feature of metastatic cancer. While many microRNAs have been implicated as regulators of metastatic progression, less is known about the roles and mechanisms of RNA-binding proteins in this process. We identified muscleblind-like 1 (MBNL1), a gene implicated in myotonic dystrophy, as a robust suppressor of multiorgan breast cancer metastasis. MBNL1 binds the 3' untranslated regions (UTRs) of DBNL (drebrin-like protein) and TACC1 (transforming acidic coiled-coil containing protein 1)-two genes that we implicate as metastasis suppressors. By enhancing the stability of these genes' transcripts, MBNL1 suppresses cell invasiveness. Consistent with these findings, elevated MBNL1 expression in human breast tumors is associated with reduced metastatic relapse likelihood. Our findings delineate a post-transcriptional network that governs breast cancer metastasis through RNA-binding protein-mediated transcript stabilization.
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Search for exotic decays of a Higgs boson into undetectable particles and one or more photons
PHYSICS LETTERS B 2016 FEB 10; 753(?):363-388
A search is presented for exotic decays of a Higgs boson into undetectable particles and one or two isolated photons in pp collisions at a center-of-mass energy of 8 TeV. The data correspond to an integrated luminosity of up to 19.4 fb(-1) collected with the CMS detector at the LHC. Higgs bosons produced in gluon-gluon fusion and in association with a Z boson are investigated, using models in which the Higgs boson decays into a gravitino and a neutralino or a pair of neutralinos, followed by the decay of the neutralino to a gravitino and a photon. The selected events are consistent with the background-only hypothesis, and limits are placed on the product of cross sections and branching fractions. Assuming a standard model Higgs boson production cross section, a 95% confidence level upper limit is set on the branching fraction of a 125 GeV Higgs boson decaying into undetectable particles and one or two isolated photons as a function of the neutralino mass. For this class of models and neutralino masses from 1 to 120 GeV an upper limit in the range of 7 to 13% is obtained. Further results are given as a function of the neutralino lifetime, and also for a range of Higgs boson masses. (C) 2015 CERN for the benefit of the CMS Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
David CJ, Huang YH, Chen M, Su J, Zou YL, Bardeesy N, Iacobuzio-Donahue CA, Massague J
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TGF-beta Tumor Suppression through a Lethal EMT
CELL 2016 FEB 25; 164(5):1015-1030
TGF-beta signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-beta mediator Smad4. We show that TGF-beta induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-beta-sensitive PDA cells, EMT becomes lethal by converting TGF-beta-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-beta. TGF-beta-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-beta tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.
Cross FR
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Tying Down Loose Ends in the Chlamydomonas Genome: Functional Significance of Abundant Upstream Open Reading Frames
G3-GENES GENOMES GENETICS 2016 FEB 1; 6(2):435-446
The Chlamydomonas genome has been sequenced, assembled, and annotated to produce a rich resource for genetics and molecular biology in this well-studied model organism. The annotated genome is very rich in open reading frames upstream of the annotated coding sequence ('uORFs'): almost three quarters of the assigned transcripts have at least one uORF, and frequently more than one. This is problematic with respect to the standard 'scanning' model for eukaryotic translation initiation. These uORFs can be grouped into three classes: class 1, initiating in-frame with the coding sequence (CDS) (thus providing a potential in-frame N-terminal extension); class 2, initiating in the 59 untranslated sequences (5UT) and terminating out-of-frame in the CDS; and class 3, initiating and terminating within the 5UT. Multiple bioinformatics criteria (including analysis of Kozak consensus sequence agreement and BLASTP comparisons to the closely related Volvox genome, and statistical comparison to cds and to random sequence controls) indicate that of similar to 4000 class 1 uORFs, approximately half are likely in vivo translation initiation sites. The proposed resulting N-terminal extensions in many cases will sharply alter the predicted biochemical properties of the encoded proteins. These results suggest significant modifications in similar to 2000 of the similar to 20,000 transcript models with respect to translation initiation and encoded peptides. In contrast, class 2 uORFs may be subject to purifying selection, and the existent ones (surviving selection) are likely inefficiently translated. Class 3 uORFs are found in more than half of transcripts, frequently multiple times per transcript; however, they are remarkably similar to random sequence expectations with respect to size, number, and composition, and therefore may in most cases be selectively neutral.
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A, Luckey PD, Marini AC, Mcginn C, Mironov C, Niu X, Paus C, Ralph D, Roland C, Roland G, Salfeld-Nebgen J, Stephans GSF, Sumorok K, Varma M, Velicanu D, Veverka J, Wang J, Wang TW, Wyslouch B, Yang M, Zhukova V, Dahmes B, Finkel A, Gude A, Hansen P, Kalafut S, Kao SC, Klapoetke K, Kubota Y, Lesko Z, Mans J, Nourbakhsh S, Ruckstuhl N, Rusack R, Tambe N, Turkewitz J, Acosta JG, Oliveros S, Avdeeva E, Bloom K, Bose S, Claes DR, Dominguez A, Fangmeier C, Suarez RG, Kamalieddin R, Keller J, Knowlton D, Kravchenko I, Lazo-Flores J, Meier F, Monroy J, Ratnikov F, Siado JE, Snow GR, Alyari M, Dolen J, George J, Godshalk A, Harrington C, Iashvili I, Kaisen J, Kharchilava A, Kumar A, Rappoccio S, Alverson G, Barberis E, Baumgartel D, Chasco M, Hortiangtham A, Knapp B, Massironi A, Morse DM, Nash D, Orimoto T, De Lima RT, Trocino D, Wang RJ, Wood D, Zhang J, Hahn KA, Kubik A, Mucia N, Odell N, Pollack B, Pozdnyakov A, Schmitt M, Stoynev S, Sung K, Trovato M, Velasco M, Brinkerhoff A, Dev N, Hildreth M, Jessop C, Karmgard DJ, Kellams N, Lannon K, Lynch S, Marinelli N, Meng F, Mueller C, Musienko Y, Pearson T, Planer M, Reinsvold A, Ruchti R, Smith G, Taroni S, Valls N, Wayne M, Wolf M, Woodard A, Antonelli L, Brinson J, Bylsma B, Durkin LS, Flowers S, Hart A, Hill C, Hughes R, Kotov K, Ling TY, Liu B, Luo W, Puigh D, Rodenburg M, Winer BL, Wulsin HW, Driga O, Elmer P, Hardenbrook J, Hebda P, Koay SA, Lujan P, Marlow D, Medvedeva T, Mooney M, Olsen J, Palmer C, Piroue P, Quan X, Saka H, Stickland D, Tully C, Werner JS, Zuranski A, Malik S, Barnes VE, Benedetti D, Bortoletto D, Gutay L, Jha MK, Jones M, Jung K, Kress M, Miller DH, Neumeister N, Radburn-Smith BC, Shi X, Shipsey I, Silvers D, Sun J, Svyatkovskiy A, Wang F, Xie W, Xu L, Parashar N, Stupak J, Adair A, Akgun B, Chen Z, Ecklund KM, Geurts FJM, Guilbaud M, Li W, Michlin B, Northup M, Padley BP, Redjimi R, Roberts J, Rorie J, Tu Z, Zabel J, Betchart B, Bodek A, de Barbaro P, Demina R, Eshaq Y, Ferbel T, Galanti M, Garcia-Bellido A, Goldenzweig P, Han J, Harel A, Hindrichs O, Khukhunaishvili A, Petrillo G, Verzetti M, Demortier L, Arora S, Barker A, Chou JP, Contreras-Campana C, Contreras-Campana E, Duggan D, Ferencek D, Gershtein Y, Gray R, Halkiadakis E, Hidas D, Hughes E, Kaplan S, Elayavalli RK, Lath A, Nash K, Panwalkar S, Park M, Salur S, Schnetzer S, Sheffield D, Somalwar S, Stone R, Thomas S, Thomassen P, Walker M, Foerster M, Riley G, Rose K, Spanier S, York A, Bouhali O, Hernandez AC, Dalchenko M, De Mattia M, Delgado A, Dildick S, Eusebi R, Flanagan W, Gilmore J, Kamon T, Krutelyov V, Montalvo R, Mueller R, Osipenkov I, Pakhotin Y, Patel R, Perloff A, Roe J, Rose A, Safonov A, Tatarinov A, Ulmer KA, Akchurin N, Cowden C, Damgov J, Dragoiu C, Dudero PR, Faulkner J, Kunori S, Lamichhane K, Lee SW, Libeiro T, Undleeb S, Volobouev I, Appelt E, Delannoy AG, Greene S, Gurrola A, Janjam R, Johns W, Maguire C, Mao Y, Melo A, Ni H, Sheldon P, Snook B, Tuo S, Velkovska J, Xu Q, Arenton MW, Boutle S, Cox B, Francis B, Goodell J, Hirosky R, Ledovskoy A, Li H, Lin C, Neu C, Wolfe E, Wood J, Xia F, Clarke C, Harr R, Karchin PE, Don CKK, Lamichhane P, Sturdy J, Belknap DA, Carlsmith D, Cepeda M, Christian A, Dasu S, Dodd L, Duric S, Friis E, Gomber B, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Lanaro A, Levine A, Long K, Loveless R, Mohapatra A, Ojalvo I, Perry T, Pierro GA, Polese G, Ross I, Ruggles T, Sarangi T, Savin A, Sharma A, Smith N, Smith WH, Taylor D, Woods N
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Angular analysis of the decay B-0 -> K*(0)mu(+)mu(-) from pp collisions at root s=8 TeV
PHYSICS LETTERS B 2016 FEB 10; 753(?):424-448
The angular distributions and the differential branching fraction of the decay B-0 -> K*(892)(0)mu(+)mu(-) are studied using data corresponding to an integrated luminosity of 20.5 fb(-1) collected with the CMS detector at the LHC in pp collisions at root s = 8 TeV. From 1430 signal decays, the forward-backward asymmetry of the muons, the K*(892)(0) longitudinal polarization fraction, and the differential branching fraction are determined as a function of the dimuon invariant mass squared. The measurements are among the most precise to date and are in good agreement with standard model predictions. (C) 2015 CERN for the benefit of the CMS Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
von Beeren C, Maruyama M, Kronauer DJC
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Cryptic diversity, high host specificity and reproductive synchronization in army ant-associated Vatesus beetles
MOLECULAR ECOLOGY 2016 FEB; 25(4):990-1005
Army ants and their arthropod symbionts represent one of the most species-rich animal associations on Earth, and constitute a fascinating example of diverse host-symbiont interaction networks. However, despite decades of research, our knowledge of army ant symbionts remains fragmentary due to taxonomic ambiguity and the inability to study army ants in the laboratory. Here, we present an integrative approach that allows us to reliably determine species boundaries, assess biodiversity, match different developmental stages and sexes, and to study the life cycles of army ant symbionts. This approach is based on a combination of community sampling, DNA barcoding, morphology and physiology. As a test case, we applied this approach to the staphylinid beetle genus Vatesus and its different Eciton army ant host species at La Selva Biological Station, Costa Rica. DNA barcoding led to the discovery of cryptic biodiversity and, in combination with extensive community sampling, revealed strict host partitioning with no overlap in host range. Using DNA barcoding, we were also able to match the larval stages of all focal Vatesus species. In combination with studies of female reproductive physiology, this allowed us to reconstruct almost the complete life cycles of the different beetle species. We show that Vatesus beetles are highly adapted to the symbiosis with army ants, in that their reproduction and larval development are synchronized with the stereotypical reproductive and behavioural cycles of their host colonies. Our approach can now be used to study army ant-symbiont communities more broadly, and to obtain novel insights into co-evolutionary and ecological dynamics in species-rich host-symbiont systems.
Kellner N, Schwarz J, Sturm M, Fernandez-Martinez J, Griesel S, Zhang WZ, Chait BT, Rout MP, Kuck U, Hurt E
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Developing genetic tools to exploit Chaetomium thermophilum for biochemical analyses of eukaryotic macromolecular assemblies
SCIENTIFIC REPORTS 2016 FEB 11; 6(?):? Article 20937
We describe a method to genetically manipulate Chaetomium thermophilum, a eukaryotic thermophile, along with various biochemical applications. The transformation method depends on a thermostable endogenous selection marker operating at high temperatures combined with chromosomal integration of target genes. Our technique allows exploiting eukaryotic thermophiles as source for purifying thermostable native macromolecular complexes with an emphasis on the nuclear pore complex, holding great potential for applications in basic science and biotechnology.
Tsou LK, Lara-Tejero M, RoseFigura J, Zhang ZRJ, Wang YC, Yount JS, Lefebre M, Dossa PD, Kato J, Guan FL, Lam W, Cheng YC, Galan JE, Hang HC
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Antibacterial Flavonoids from Medicinal Plants Covalently Inactivate Type III Protein Secretion Substrates
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 2016 FEB 24; 138(7):2209-2218
Traditional Chinese Medicines (TCMs) have been historically used to treat bacterial infections. However, the molecules responsible for these anti-infective properties and their potential mechanisms of action have remained elusive. Using a high-throughput assay for type III protein secretion in Salmonella enterica serovar Typhimurium, we discovered that several TCMs can attenuate this key virulence pathway without affecting bacterial growth. Among the active TCMs, we discovered that baicalein, a specific flavonoid from Scutellaria baicalensis, targets S. Typhimurium pathogenicity island-1 (SPI-1) type III secretion system (T3SS) effectors and translocases to inhibit bacterial invasion of epithelial cells. Structurally related flavonoids present in other TCMs, such as quercetin, also inactivated the SPI-1 T3SS and attenuated S. Typhimurium invasion. Our results demonstrate that specific plant metabolites from TCMs can directly interfere with key bacterial virulence pathways and reveal a previously unappreciated mechanism of action for anti-infective medicinal plants.
Nguyen A, Loo JM, Mital R, Weinberg EM, Man FY, Zeng ZS, Paty PB, Saltz L, Janjigian YY, de Stanchina E, Tavazoie SF
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PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis
JOURNAL OF CLINICAL INVESTIGATION 2016 FEB; 126(2):681-694
Colorectal cancer metastasis to the liver is a major cause of cancer-related death; however, the genes and pathways that govern this metastatic colonization event remain poorly characterized. Here, using a large-scale in vivo RNAi screen, we identified liver and red blood cell pyruvate kinase (PKLR) as a driver of metastatic liver colonization. PKLR expression was increased in liver metastases as well as in primary colorectal tumors of patients with metastatic disease. Evaluation of a murine liver colonization model revealed that PKLR promotes cell survival in the tumor core during conditions of high cell density and oxygen deprivation by increasing glutathione, the primary endogenous antioxidant. PKLR negatively regulated the glycolytic activity of PKM2, the major pyruvate kinase isoenzyme known to regulate cellular glutathione levels. Glutathione is critical for metastasis, and we determined that the rate-limiting enzyme of glutathione synthesis, GCLC, becomes overexpressed in patient liver metastases, promotes cell survival under hypoxic and cell-dense conditions, and mediates metastatic liver colonization. RNAi-mediated inhibition of glutathione synthesis impaired survival of multiple colon cancer cell lines, and pharmacological targeting of this metabolic pathway reduced colonization in a primary patient-derived xenograft model. Our findings highlight the impact of metabolic reprogramming within the niche as metastases progress and suggest clinical potential for targeting this pathway in colorectal cancer.
Aaltonen T, Amerioa S, Amidei D, Anastassov A, Annovi A, Antos J, Apollinari G, Appel JA, Arisawa T, Artikov A, Asaadi J, Ashmanskas W, Auerbach B, Aurisano A, Azfar F, Badgett W, Bae T, Barbaro-Galtieri A, Barnes VE, Barnett BA, Barria P, Bartos P, Bauce M, Bedeschi F, Behari S, Bellettini G, Bellinger J, Benjamin D, Beretvas A, Bhatti A, Bland KR, Blumenfeld B, Bocci A, Bodek A, Bortoletto D, Boudreau J, Boveia A, Brigliadori L, Bromberg C, Brucken E, Budagov J, Budd HS, Burkett K, Busetto G, Bussey P, Butti P, Buzatu A, Calamba A, Camarda S, Campanelli M, Canelli F, Carls B, Carlsmith D, Carosi R, Carrillo S, Casal B, Casarsa M, Castro A, Catastini P, Cauz D, Cavaliere V, Cerri A, Cerrito L, Chen YC, Chertok M, Chiarelli G, Chlachidze G, Cho K, Chokheli D, Clark A, Clarke C, Convery ME, Conway J, Corbo M, Cordelli M, Cox CA, Cox DJ, Cremonesi M, Cruz D, Cuevas J, Culbertson R, d'Ascenzo N, Datta M, De Barbaro P, Demortier L, Deninno M, D'Errico M, Devoto F, Di Canto A, Di Ruzza B, Dittmann JR, Donati S, D'Onofrio M, Dorigo M, Driutti A, Ebina K, Edgar R, Elagin A, Erbacher R, Errede S, Esham B, Farrington S, Ramos JPF, Field R, Flanagan G, Forrest R, Franklin M, Freeman JC, Frisch H, Funakoshi Y, Galloni C, Garfinkel AF, Garosi P, Gerberich H, Gerchtein E, Giagu S, Giakoumopoulou V, Gibson K, Ginsburg CM, Giokaris N, Giromini P, Glagolev V, Glenzinski D, Gold M, Goldin D, Golossanov A, Gomez G, Gomez-Ceballos G, Goncharov M, Lopez OG, Gorelov I, Goshaw AT, Goulianos K, Gramellini E, Grosso-Pilcher C, Group RC, da Costa JG, Hahn SR, Han JY, Happacher F, Hara K, Hare M, Harr RF, Harrington-Taber T, Hatakeyama K, Hays C, Heinrich J, Herndon M, Hocker A, Hong Z, Hopkins W, Hou S, Hughes RE, Husemann U, Hussein M, Huston J, Introzzi G, Iori M, Ivanov A, James E, Jang D, Jayatilaka B, Jeon EJ, Jindariani S, Jones M, Joo KK, Jun SY, Junk TR, Kambeitz M, Kamon T, Karchin PE, Kasmi A, Kato Y, Ketchum W, Keung J, Kilminster B, Kim DH, Kim HS, Kim JE, Kim MJ, Kim SH, Kim SB, Kim YJ, Kim YK, Kimura N, Kirby M, Knoepfel K, Kondo K, Kong DJ, Konigsberg J, Kotwal AV, Kreps M, Kroll J, Kruse M, Kuhr T, Kurata M, Laasanen AT, Lammel S, Lancaster M, Lannon K, Latino G, Lee HS, Lee JS, Leo S, Leone S, Lewis JD, Limosani A, Lipeles E, Lister A, Liu H, Liu Q, Liu T, Lockwitz S, Loginov A, Lucchesi D, Luca A, Lueck J, Lujan P, Lukens P, Lungu G, Lys J, Lysak R, Madrak R, Maestro P, Malik S, Manca G, Manousakis-Katsikakis A, Marchese L, Margaroli F, Marino P, Matera K, Mattson ME, Mazzacane A, Mazzanti P, McNulty R, Mehta A, Mehtala P, Mesropian C, Miao T, Mietlicki D, Mitra A, Miyake H, Moed S, Moggi N, Moon CS, Moore R, Morello MJ, Mukherjee A, Muller T, Murat P, Mussini M, Nachtman J, Nagai Y, Naganoma J, Nakano I, Napier A, Nett J, Neu C, Nigmanov T, Nodulman L, Noh SY, Norniella O, Oakes L, Oh SH, Oh YD, Oksuzian I, Okusawa T, Orava R, Ortolan L, Pagliarone C, Palencia E, Palni P, Papadimitriou V, Parker W, Pauletta G, Paulini M, Paus C, Phillips TJ, Pianori E, Pilot J, Pitts K, Plager C, Pondrom L, Poprocki S, Potamianos K, Pranko A, Prokoshin F, Ptohos F, Punzi G, Fernandez IR, Renton P, Rescigno M, Rimondi F, Ristori L, Robson A, Rodriguez T, Rolli S, Ronzani M, Roser R, Rosner L, Ruffini F, Ruiz A, Russ J, Rusu V, Sakumoto WK, Sakurai Y, Santi L, Sato K, Saveliev V, Savoy-Navarro A, Schlabach P, Schmidt EE, Schwarz T, Scodellaro L, Scuri F, Seidel S, Seiya Y, Semenov A, Sforza F, Shalhout SZ, Shears T, Shepard PF, Shimojima M, Shochet M, Shreyber-Tecker I, Simonenko A, Sliwa K, Smith JR, Snider FD, Song H, Sorin V, St Denis R, Stancari M, Stentz D, Strologas J, Sudo Y, Sukhanov A, Suslov I, Takemasa K, Takeuchi Y, Tang J, Tecchio M, Teng PK, Thom J, Thomson E, Thukral V, Toback D, Tokar S, Tollefson K, Tomura T, Tonelli D, Torre S, Torretta D, Totaro P, Trovato M, Ukegawa F, Uozumi S, Vazquez F, Velev G, Vellidis C, Vernieri C, Vidal M, Vilar R, Vizan J, Vogel M, Volpi, Wagner P, Wallny R, Wang SM, Waters D, Wester WC, Whiteson D, Wicklund AB, Wilbur S, Williams HH, Wilson JS, Wilson P, Winer BL, Wittich P, Wolbers S, Wolfe H, Wright T, Wu X, Wu Z, Yamamoto K, Yamato D, Yang T, Yang UK, Yang YC, Yao WM, Yeh GP, Yi K, Yoh J, Yorita K, Yoshida T, Yu GB, Yu I, Zanetti AM, Zeng Y, Zhou C, Zucchellia S
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Measurement of the single top quark production cross section and vertical bar V-tb vertical bar in 1.96 TeV p(p)over-bar collisions with missing transverse energy and jets and final CDF combination
PHYSICAL REVIEW D 2016 FEB 26; 93(3):? Article 032011
An updated measurement of the single top quark production cross section is presented using the full data set collected by the Collider Detector at Fermilab (CDF), corresponding to 9.5 fb(-1) of integrated luminosity from proton-antiproton collisions at 1.96 TeV center-of-mass energy. The events selected contain an imbalance in the total transverse momentum, jets identified as containing b quarks, and no identified leptons. The sum of the s- and t-channel single top quark cross sections is measured to be 3.53(-1.16)(+1.25) pb and a lower limit on the magnitude of the top-to-bottom quark coupling, vertical bar V-tb vertical bar of 0.63, is obtained at the 95% credibility level. These measurements are combined with previously reported CDF results obtained from events with an imbalance in total transverse momentum, jets identified as originating from b quarks, and one identified lepton. The combined cross section is measured to be 3.02(-0.48)(+0.49) pb and a lower limit on vertical bar V-tb vertical bar of 0.84 is obtained at the 95% credibility level.