Transcript [Science] 31 MAY 2013 VOL 340, ISSUE 6136, PAGES 1005-1132

[Science] 31 MAY 2013 VOL 340, ISSUE 6136, PAGES 1005-1132
EDITORIAL: After 5 Years at Science
Bruce Alberts
Science 31 May 2013: 1015. Podcast Interview
Perspectives-CELL BIOLOGY
Vitamin Currency in a Lipid Exchange Market
Bruno Mesmin and Bruno Antonny
Science 31 May 2013: 1051-1052.
A lipid transfer protein moves vitamin E through the cell to the cell surface by exchanging it for a phosphoinositide in the
plasma membrane.
Science. 2013 May 31;340(6136):1106-10. doi: 10.1126/science.1233508. Epub 2013 Apr 18.
Impaired α-TTP-PIPs interaction underlies familial vitamin E deficiency.
Kono N, Ohto U, Hiramatsu T, Urabe M, Uchida Y, Satow Y, Arai H.
Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
α-Tocopherol (vitamin E) transfer protein (α-TTP) regulates the secretion of α-tocopherol from liver cells. Missense
mutations of some arginine residues at the surface of α-TTP cause severe vitamin E deficiency in humans, but the role of
these residues is unclear. Here, we found that wild-type α-TTP bound phosphatidylinositol phosphates (PIPs), whereas the
arginine mutants did not. In addition, PIPs in the target membrane promoted the intermembrane transfer of α-tocopherol
by α-TTP. The crystal structure of the α-TTP-PIPs complex revealed that the disease-related arginine residues interacted
with phosphate groups of the PIPs and that the PIPs binding caused the lid of the α-tocopherol-binding pocket to open.
Thus, PIPs have a role in promoting the release of a ligand from a lipid-transfer protein.
[Science] 31 MAY 2013 VOL 340, ISSUE 6136, PAGES 1005-1132
Perspectives - CELL BIOLOGY
GATORs Take a Bite Out of mTOR
Reuben J. Shaw
Science 31 May 2013: 1056-1057.
A negative regulator of amino acid sensing by the mTOR signaling pathway is identified and discovered to be inactivated
in cancers.
Science. 2013 May 31;340(6136):1100-6. doi: 10.1126/science.1232044.
A Tumor suppressor complex with GAP activity for the Rag GTPases
that signal amino acid sufficiency tomTORC1.
Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM.
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Cambridge, MA 02142, USA.
The mTOR complex 1 (mTORC1) pathway promotes cell growth in response to many cues, including amino acids, which act
through the Ragguanosine triphosphatases (GTPases) to promote mTORC1 translocation to the lysosomal surface, its site of
activation. Although progress has been made in identifying positive regulators of the Rags, it is unknown if negative factors
also exist. Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we
call GATOR1 and -2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant
to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, and Sec13)
suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has
GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. In cancer
cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells
are hypersensitive to rapamycin, an mTORC1inhibitor. Thus, we identify a key negative regulator of the Rag GTPases and
reveal that, like other mTORC1 regulators, Rag function can be deregulated in cancer
[Science] 31 MAY 2013 VOL 340, ISSUE 6136, PAGES 1005-1132
A Conserved Mechanism for Centromeric Nucleosome Recognition by Centromere Protein CENP-C
Hidenori Kato, Jiansheng Jiang, Bing-Rui Zhou, Marieke Rozendaal, Hanqiao Feng, Rodolfo Ghirlando, T. Sam Xiao, Aaron F. Straight, and Yawen Bai
Science 31 May 2013: 1110-1113.
The structural links between the chromosomal centromere protein CenH3 and the kinetochore protein CENP-C are
determined.
Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody
Jason S. McLellan, Man Chen, Sherman Leung, Kevin W. Graepel, Xiulian Du, Yongping Yang, Tongqing Zhou, Ulrich Baxa,Etsuko Yasuda, Tim
Beaumont, Azad Kumar, Kayvon Modjarrad, Zizheng Zheng, Min Zhao, Ningshao Xia, Peter D. Kwong,and Barney S. Graham
Science 31 May 2013: 1113-1117.
The prefusion conformation of respiratory syncytial virus protein F has been trapped by a neutralizing antibody.
Tracking Individuals Shows Spatial Fidelity Is a Key Regulator of Ant Social Organization
Danielle P. Mersch, Alessandro Crespi, and Laurent Keller
Science 31 May 2013: 1090-1093.
Monitoring of individually tagged worker ants revealed three distinct groups that greatly differ in behavior.
Mechanisms of Age-Dependent Response to Winter Temperature in Perennial Flowering of Arabis
alpina
Sara Bergonzi, Maria C. Albani, Emiel Ver Loren van Themaat, Karl J. V. Nordström, Renhou Wang, Korbinian Schneeberger,
Perry D. Moerland, and George Coupland
Science 31 May 2013: 1094-1097.
MicroRNAs regulate perennial flowering.
Molecular Basis of Age-Dependent Vernalization in Cardamine flexuosa
Chuan-Miao Zhou, Tian-Qi Zhang, Xi Wang, Sha Yu, Heng Lian, Hongbo Tang, Zheng-Yan Feng, Judita Zozomova-Lihová,
and Jia-Wei Wang
Science 31 May 2013: 1097-1100.
MicroRNAs regulate perennial flowering.
[Science Sig] 28 MAY 2013 VOL 6, ISSUE 277
[Science Trans Med] 29 MAY 2013 VOL 5, ISSUE 187
Sci Transl Med. 2013 May 29;5(187):187ra71. doi: 10.1126/scitranslmed.3005688.
A preclinical xenograft model identifies castration-tolerant cancer-repopulating cells
in localized prostatetumors.
Toivanen R, Frydenberg M, Murphy D, Pedersen J, Ryan A, Pook D, Berman DM; Australian Prostate Cancer BioResource, Taylor RA, Risbridger GP.
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
A lack of clinically relevant experimental models of human prostate cancer hampers evaluation of potential therapeutic
agents. Currently, androgen deprivation therapy is the gold standard treatment for advanced prostate cancer, but inevitably,
a subpopulation of cancer cellssurvives and repopulates the tumor. Tumor cells that survive androgen withdrawal are
critical therapeutic targets for more effective treatments, but current model systems cannot determine when they arise in
disease progression and are unable to recapitulate variable patient response to treatment. A model system was developed
in which stromal-supported xenografts from multiple patients with early-stage localized disease can be tested for response
to castration. The histopathology of these xenografts mimicked the original tumors, and short-term host castration resulted
in reduced proliferation and increased apoptosis in tumor cells. After 4 weeks of castration, residual populations of
quiescent, stem-like tumor cellsremained. Without subsequent treatment, these residual cells displayed regenerative
potential, because testosterone readministration resulted in emergence of rapidly proliferating tumors. Therefore,
this model may be useful for revealing potential cellular targets in prostate cancer, which exist before the onset of
aggressive incurable disease. Specific eradication of these regenerative tumor cells that survive castration could then confer
survival benefits for patients.
DRUG TOXICITY
Coronary Microvascular Pericytes Are the Cellular Target of Sunitinib Malate–Induced Cardiotoxicity
Vishnu Chintalgattu, Meredith L. Rees, James C. Culver, Aditya Goel, Tilahu Jiffar, Jianhu Zhang, Kenneth Dunner, Jr.,
Shibani Pati,James A. Bankson, Renata Pasqualini, Wadih Arap, Nathan S. Bryan, Heinrich Taegtmeyer, Robert R. Langley,
Hui Yao,Michael E. Kupferman, Mark L. Entman, Mary E. Dickinson, and Aarif Y. Khakoo
Sunitinib-induced cardiotoxicity is caused by depletion of coronary pericytes due to loss of PDGFR signaling; this side
effect can be prevented by thalidomide.
KJ
Wnt Signaling Regulates the Lineage Differentiation Potential of Mouse
Embryonic Stem Cells through Tcf3 Down-Regulation
Yaser Atlasi, X Rubina Noori, X Claudia Gaspar, X Patrick Franken, X Andrea Sacchetti, X Haleh Rafati, X
Tokameh Mahmoudi, X Charles Decraene, X George A. Calin, X Bradley J. Merrill, X Riccardo Fodde
Abstract
Canonical Wnt signaling plays a rate-limiting role in regulating self-renewal and differentiation in mouse
embryonic stem cells (ESCs). We have previously shown that mutation in the Apc (adenomatous polyposis
coli) tumor suppressor gene constitutively activates Wnt signaling in ESCs and inhibits their capacity to
differentiate towards ecto-, meso-, and endodermal lineages. However, the underlying molecular and cellular
mechanisms through which Wnt regulates lineage differentiation in mouse ESCs remain to date largely
unknown. To this aim, we have derived and studied the gene expression profiles of several Apc-mutant ESC
lines encoding for different levels of Wnt signaling activation. We found that down-regulation of Tcf3, a
member of the Tcf/Lef family and a key player in the control of self-renewal and pluripotency, represents a
specific and primary response to Wnt activation in ESCs. Accordingly, rescuing Tcf3 expression partially
restored the neural defects observed in Apc-mutant ESCs, suggesting that Tcf3 down-regulation is a
necessary step towards Wnt-mediated suppression of neural differentiation. We found that Tcf3 downregulation in the context of constitutively active Wnt signaling does not result from promoter DNA
methylation but is likely to be caused by a plethora of mechanisms at both the RNA and protein level as
shown by the observed decrease in activating histone marks (H3K4me3 and H3-acetylation) and the
upregulation of miR-211, a novel Wnt-regulated microRNA that targets Tcf3 and attenuates early neural
differentiation in mouse ESCs. Our data show for the first time that Wnt signaling down-regulates Tcf3
expression, possibly at both the transcriptional and post-transcriptional levels, and thus highlight a novel
mechanism through which Wnt signaling inhibits neuro-ectodermal lineage differentiation in mouse
embryonic stem cells.
KJ
KJ
KJ
Developmental Immunology and Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard
Medical School, Boston, Massachusetts, USA.
Phagocytosis is a fundamental cellular process that is pivotal for immunity as it coordinates microbial killing,
innate immune activation and antigen presentation. An essential step in this process is phagosome acidification,
which regulates many functions of these organelles that allow phagosomes to participate in processes that are
essential to both innate and adaptive immunity. Here we report that acidification of phagosomes containing
Gram-positive bacteria is regulated by the NLRP3 inflammasome and caspase-1. Active caspase-1 accumulates on
phagosomes and acts locally to control the pH by modulating buffering by the NADPH oxidase NOX2. These data
provide insight into a mechanism by which innate immune signals can modify cellular defenses and establish a new
function for the NLRP3 inflammasome and caspase-1 in host defense.
Wnt Signaling Regulates the Lineage Differentiation Potential of Mouse
Embryonic Stem Cells through Tcf3 Down-Regulation
Yaser Atlasi1, Rubina Noori1, Claudia Gaspar1¤, Patrick Franken1, Andrea Sacchetti1, Haleh Rafati2, Tokameh Mahmoudi2,
Charles Decraene3,4, George A. Calin5, Bradley J. Merrill6, Riccardo Fodde1*
1 Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands, 2 Department of Biochemistry, Erasmus
MC, Rotterdam, The Netherlands, 3 Translational Research Department, Institut Curie, Centre de Recherche, Paris, France, 4 CNRS,
UMR144, Paris, France, 5 Department of Experimental
Therapeutics and Center for RNA Interference and Non-Coding RNAs, MD Anderson Cancer Center, Houston, Texas, United States of
America, 6 Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois, United States of America
Abstract
Canonical Wnt signaling plays a rate-limiting role in regulating self-renewal and differentiation in mouse embryonic ste
m cells (ESCs). We have previously shown that mutation in the Apc (adenomatous polyposis coli) tumor suppressor gen
e constitutively activates Wnt signaling in ESCs and inhibits their capacity to differentiate towards ecto-, meso-, and end
odermal lineages. However, the underlying molecular and cellular mechanisms through which Wnt regulates lineage dif
ferentiation in mouse ESCs remain to date largely unknown. To this aim, we have derived and studied the gene expressi
on profiles of several Apc-mutant ESC lines encoding for different levels of Wnt signaling activation. We found that dow
n-regulation of Tcf3, a member of the Tcf/Lef family and a key player in the control of self-renewal and pluripotency, re
presents a specific and primary response to Wnt activation in ESCs. Accordingly, rescuing Tcf3 expression partially restor
ed the neural defects observed in Apc-mutant ESCs, suggesting that Tcf3 down-regulation is a necessary step towards
Wnt-mediated suppression of neural differentiation. We found that Tcf3 down-regulation in the context of constitutivel
y active Wnt signaling does not result from promoter DNA methylation but is likely to be caused by a plethora of mech
anisms at both the RNA and protein level as shown by the observed decrease in activating histone marks (H3K4me3 an
d H3-acetylation) and the upregulation of miR-211, a novel Wnt-regulated microRNA that targets Tcf3 and attenuates e
arly neural differentiation in mouse ESCs. Our data show for the first time that Wnt signaling down-regulates Tcf3 expre
ssion, possibly at both the transcriptional and post-transcriptional levels, and thus highlight a novel mechanism through
which Wnt signaling inhibits neuro-ectodermal lineage differentiation in mouse embryonic stem cells.
Interactions with Iridophores and the Tissue Environment Required f
or Patterning Melanophores and Xanthophores during Zebrafish Adu
lt Pigment Stripe Formation Larissa B. Patterson, David M. Parichy
CDK4 T172 Phosphorylation Is Central in a CDK7-Dependent Bidirect
ional CDK4/CDK2 Interplay Mediated by p21 Phosphorylation at the
Restriction Point Xavier Bisteau, Sabine Paternot, Bianca Colleoni, K
arin Ecker, Katia Coulonval, Philippe De Groote, Wim Declercq, Ludg
er Hengst, Pierre P. Roger
DNA Binding of the Cell Cycle Transcriptional Regulator GcrA Depen
ds on N6-Adenosine Methylation in Caulobacter crescentus and Othe
r Alphaproteobacteria
Antonella Fioravanti, Coralie Fumeaux, Saswat S. Mohapatra, Coralie
Bompard, Matteo Brilli, Antonio Frandi, Vincent Castric, Vincent Ville
ret, Patrick H. Viollier, Emanuele G. Biondi
Cell Polarity and Patterning by PIN Trafficking through Early Endoso
mal Compartments in Arabidopsis thaliana
Hirokazu Tanaka, Saeko Kitakura, Hana Rakusová, Tomohiro Uemura
, Mugurel I. Feraru, Riet De Rycke, Stéphanie Robert, Tatsuo Kakimot
o, Jiří Friml
GLIS3, a Susceptibility Gene for Type 1 and Type 2 Diabetes, Modulat
es Pancreatic Beta Cell Apoptosis via Regulation of a Splice Variant
of the BH3-Only Protein Bim Tatiane C. Nogueira, Flavia M. Paula, Ol
atz Villate, Maikel L. Colli, Rodrigo F. Moura, Daniel A. Cunha, Lorella
Marselli, Piero Marchetti, Miriam Cnop, Cécile Julier, Decio L. Eizirik
Side Effects: Substantial Non-Neutral Evolution Flanking Regulatory
Sites James G. D. Prendergast, Colin A.
Strong Purifying Selection at Synonymous Sites in D. melan
ogaster David S. Lawrie, Philipp W. Messer, Ruth Hershberg,
Dmitri A. Petrov
Using Extended Genealogy to Estimate Components of Herit
ability for 23 Quantitative and Dichotomous Traits
Noah Zaitlen, Peter Kraft, Nick Patterson, Bogdan Pasaniuc,
Gaurav Bhatia, Samuela Pollack, Alkes L. Price
Drosophila Functional Elements Are Embedded in Structural
ly Constrained Sequences
Ephraim Kenigsberg, Amos Tanay
Global Properties and Functional Complexity of Human Gen
e Regulatory Variation Daniel J. Gaffney
From Paramutation to Paradigm
Ian R. Adams, Richard R. Meehan
Arabidopsis thaliana RESISTANCE TO FUSARIUM OXYSPO
RUM 2 Implicates Tyrosine-Sulfated Peptide Signaling in Su
sceptibility and Resistance to Root Infection
Yunping Shen, Andrew C. Diener
ttm-1 Encodes CDF Transporters That Excrete Zinc from Inte
stinal Cells of C. elegans and Act in a Parallel Negative Feed
back Circuit That Promotes Homeostasis
Hyun Cheol Roh, Sara Collier, Krupa Deshmukh, James Gut
hrie, J. David Robertson, Kerry Kornfeld
Ikbkap/Elp1 Deficiency Causes Male Infertility by Disrupting
Meiotic Progression Fu-Jung Lin, Li Shen, Chuan-Wei Jang,
Pål Ø. Falnes, Yi Zhang
RNA–Mediated Epigenetic Heredity Requires the Cytosine Methyltra
nsferase Dnmt2
Jafar Kiani, Valérie Grandjean, Reinhard Liebers, Francesca Tuorto,
Hossein Ghanbarian, Frank Lyko, François Cuzin, Minoo Rassoulzade
gan
Analysis of the Genetic Basis of Disease in the Context of Worldwid
e Human Relationships and Migration Erik Corona, Rong Chen, Mar
tin Sikora, Alexander A. Morgan, Chirag J. Patel, Aditya Ramesh, Ca
rlos D. Bustamante, Atul J. Butte
Clathrin and AP2 Are Required for Phagocytic Receptor-Mediated A
poptotic Cell Clearance in Caenorhabditis elegans Didi Chen, Youli J
ian, Xuezhao Liu, Yuanya Zhang, Jingjing Liang, Xiaying Qi, Hongwe
i Du, Wei Zou, Lianwan Chen, Yongping Chai, Guangshuo Ou, Long
Miao, Yingchun Wang, Chonglin Yang
The Secretory Pathway Calcium ATPase PMR-1/SPCA1 Has Essential
Roles in Cell Migration during Caenorhabditis elegans Embryonic D
evelopment
Vida Praitis, Jeffrey Simske, Sarah Kniss, Rebecca Mandt, Leah Imlay
, Charlotte Feddersen, Michael B. Miller, Juliet Mushi, Walter Liszew
ski, Rachel Weinstein, Adityarup Chakravorty, Dae-Gon Ha, Angela
Schacht Farrell, Alexander Sullivan-Wilson, Tyson Stock
ATM–Dependent MiR-335 Targets CtIP and Modulates the DNA Da
mage Response
Nathan T. Martin, Kotoka Nakamura, Robert Davies, Shareef A. Nah
as, Christina Brown, Rashmi Tunuguntla, Richard A. Gatti, Hailiang
Hu
HDAC7 Is a Repressor of Myeloid Genes Whose Downregul
ation Is Required for Transdifferentiation of Pre-B Cells int
o Macrophages
Bruna Barneda-Zahonero, Lidia Román-González, Olga Colla
zo, Haleh Rafati, Abul B. M. M. K. Islam, Lars H. Bussmann,
Alessandro di Tullio, Luisa De Andres, Thomas Graf, Núria L
ópez-Bigas, Tokameh Mahmoudi, Maribel Parra
Human Genetics in Rheumatoid Arthritis Guides a High-Thr
oughput Drug Screen of the CD40 Signaling Pathway
Gang Li, Dorothée Diogo, Di Wu…………………Robert M. Ple
nge
Liver X Receptors Protect from Development of Prostatic In
tra-Epithelial Neoplasia in Mice Aurélien J. C. Pommier, Juli
e Dufour, Georges Alves, Emilie Viennois, Hugues De Bouss
ac, Amalia Trousson, David H. Volle, Françoise Caira, Pierre
Val, Philippe Arnaud, Jean-Marc A. Lobaccaro, Silvère Baron
Genome-Wide Analysis in German Shepherd Dogs Reveals
Association of a Locus on CFA 27 with Atopic Dermatitis Ka
tarina Tengvall, Marcin Kierczak, Kerstin Bergvall, Mia Olsso
n, Marcel Frankowiack, Fabiana H. G. Farias, Gerli Pielberg,
Örjan Carlborg, Tosso Leeb, Göran Andersson, Lennart Ham
marström, Åke Hedhammar, Kerstin Lindblad-Toh
Wnt Signaling Regulates the Lineage Differentiation Potenti
al of Mouse Embryonic Stem Cells through Tcf3 Down-Reg
ulation Yaser Atlasi, Rubina Noori, Claudia Gaspar, Patrick F
ranken, Andrea Sacchetti, Haleh Rafati, Tokameh Mahmoud
i, Charles Decraene, George A. Calin, Bradley J. Merrill, Ricc
ardo Fodde Research Article | published 02 May 2013 | PLO
S Genetics