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| Open AccessSelective inhibition of microRNA accessibility by RBM38 is required for p53 activity
MicroRNAs bind to the 3′-untranslated region of genes to regulate expression. In this study, an RNA-binding protein, RMB38, is shown to selectively regulate the access of some microRNAs to their targets, and control the expression of some p53 target genes.
- Nicolas Léveillé
- , Ran Elkon
- & Reuven Agami
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Article
| Open AccessProliferating versus differentiating stem and cancer cells exhibit distinct midbody-release behaviour
During cell division, a cytoplasmic bridge—the midbody—forms between the nascent daughter cells, but it has been unclear under which conditions this is retained by a daughter cell or released. Now, Ettinger and colleagues show that midbody-release occurs more frequently in stem cells compared with cancer cells.
- Andreas W. Ettinger
- , Michaela Wilsch-Bräuninger
- & Wieland B. Huttner
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Article
| Open AccessThe collagen-binding protein of Streptococcus mutans is involved in haemorrhagic stroke
The risk factors associated with both ischemic and haemorrhagic stroke are not fully understood. Here a certain strain of the bacteria,Streptococcus mutans, which expresses a collagen-binding protein, is shown to be associated with haemorrhagic stroke in both animal models and human patients.
- Kazuhiko Nakano
- , Kazuya Hokamura
- & Takashi Ooshima
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p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression
Cellular senescence is characterized by the cessation of cell growth and the expression of the p16 protein. In this study, inhibition or loss of p300, a histone acetyltransferase, is shown to result in senescence that occurs independently of p16 and is associated with histone hypoacetylation and altered replication timing.
- Alexandre Prieur
- , Emilie Besnard
- & Jean-Marc Lemaitre
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Plasmonic substrates for multiplexed protein microarrays with femtomolar sensitivity and broad dynamic range
Protein microarrays are useful both in basic research and also in disease monitoring and diagnosis, but their dynamic range is limited. By using plasmonic gold substrates with near-infrared fluorescent enhancement, Tabakman et al. demonstrate a multiplexed protein array with improved detection limits and dynamic range.
- Scott M. Tabakman
- , Lana Lau
- & Hongjie Dai
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Article
| Open AccessParkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus
Pluripotent stem cells can be generated from the somatic cells of humans and are a useful model to study disease. Here, pluripotent stem cells are made from a patient with familial Parkinson's disease, and the resulting neurons exhibit elevated levels of α-synuclein, recapitulating the molecular features of the patient's disease.
- Michael J. Devine
- , Mina Ryten
- & Tilo Kunath
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Regulation of MITF stability by the USP13 deubiquitinase
MITF is a transcription factor required for melanocyte development, which is activated in some melanomas. Zhao and colleagues show that USP13 removes ubiquitin from MITF, stabilizes MITF protein levels and enhances colony formation, suggesting that USP13 may be a therapeutic target in melanoma.
- Xiansi Zhao
- , Brian Fiske
- & David E Fisher
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Article
| Open AccessToxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells
Polo-like kinase 1 is a key regulator of mitosis and is a candidate for drug development to treat cancer. Here, reduced expression of polo-like kinase 1 in adult mice has a minor impact on animal physiology, suggesting that polo-like kinase 1 inhibitors may be useful in the killing of tumour cells while sparing normal cells.
- Monika Raab
- , Sven Kappel
- & Klaus Strebhardt
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Article
| Open AccessFunctional and molecular interactions between ERK and CHK2 in diffuse large B-cell lymphoma
Chk2 is a kinase that is a potential chemotherapeutic target. Here, Chk2 and the kinase ERK are shown to functionally interact, and are elevated in expression in human diffuse B-cell lymphomas. Combinatorial inhibition of the kinases was also shown to block tumour growth in anin vivomouse model.
- Bojie Dai
- , X. Frank Zhao
- & Ronald B. Gartenhaus
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TorsinA participates in endoplasmic reticulum-associated degradation
The torsinA protein localizes to the endoplasmic reticulum and, when mutated, causes early onset torsion dystonia. The authors reveal a new role for torsinA in proteosome-mediated degradation of misfolded proteins, and relate this to endoplasmic reticulum stress, in aCaenorhabditis elegansmodel and patient fibroblasts.
- Flávia C. Nery
- , Ioanna A. Armata
- & Xandra O. Breakefield
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Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site
The sigma-2 receptor is used as a biomarker for tumour cell proliferation but its identity is unknown. Using a novel radiolabelled probe, the authors identify progesterone receptor membrane component 1, which is overexpressed in several tumour types, as the putative sigma-2 receptor.
- Jinbin Xu
- , Chenbo Zeng
- & Robert H. Mach
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Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome
Mutations in the DNA helicaseBLM cause Bloom syndrome, which is characterized by slow replication fork progression and genetic instability. Here, cells lacking BLMare shown to have a defect in cytidine deaminase, which alters the pyrimidine pool and results in replication fork progression with altered velocity.
- Pauline Chabosseau
- , Géraldine Buhagiar-Labarchède
- & Mounira Amor-Guéret
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Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels
Class I anti-arrhythmic drugs act at cardiac sodium channels and are subdivided into classes Ia-c based on their effects on the electrocardiogram. Here, class Ib drugs are found to rely on cation–pi interactions for their activity, whereas class Ib and Ic drugs rely significantly less on this interaction.
- Stephan A. Pless
- , Jason D. Galpin
- & Christopher A. Ahern
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Article
| Open AccessInteraction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites
The ability of synthetic amyloid β-protein to bind to prion proteins and alter synaptic plasticity has been previously reported. Here the relevance of this binding is investigated in brains of Alzheimer's disease patients and the interaction is shown to be blocked by antibodies to two distinct regions of prion proteins.
- Darragh B. Freir
- , Andrew J. Nicoll
- & John Collinge
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MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma
α-fetoprotein is used as a biomarker of hepatocellular cancer but the mechanisms that lead to its elevated expression are unknown. Kojimaet al.show that microRNA122 and CUX1 are important for the regulation of α-fetoprotein and suggest that loss of microRNA122 leads to more aggressive liver cancer.
- Kentaro Kojima
- , Akemi Takata
- & Kazuhiko Koike
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Article
| Open AccessTRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer
TGFβ can function as both a tumour suppressor and tumour promoter under different cellular contexts. Here, the cleavage product of the TGFβ type I receptor is shown to be generated in a TGFβ-dependent manner, and can induce the expression of genes involved in tumour cell invasion.
- Yabing Mu
- , Reshma Sundar
- & Marene Landström
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Article
| Open AccessGenetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
Complex diseases such as multiple sclerosis have both genetic and environmental components. This study demonstrates that variants of genes implicated in multiple sclerosis, and alterations in cellular metabolism and vitamin D3 levels, alterN-glycosylation, a post-translational modification causal of the disease in mice.
- Haik Mkhikian
- , Ani Grigorian
- & Michael Demetriou
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Article
| Open AccessIKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways
IKK kinases activate nuclear factor-κB, and the activated form of this transcription factor is found in endothelial cells in diseased tissue. In this study, mice lacking IKKβ in the endothelium are generated, and it is shown that defects in endothelial cell function are both IKK kinase activity dependent and independent.
- Noboru Ashida
- , Sucharita SenBanerjee
- & Anthony Rosenzweig
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Article
| Open AccessChemical treatment enhances skipping of a mutated exon in the dystrophin gene
Duchenne muscular dystrophy is caused by a loss of thedystrophin gene, and control of dystrophin mRNA splicing could aid treatment of the disease. Nishida et al. show that a small molecule promotes skipping of exon 31 and increases production of a functional dystrophin protein in a patient.
- Atsushi Nishida
- , Naoyuki Kataoka
- & Masafumi Matsuo
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α-Mannosidase 2C1 attenuates PTEN function in prostate cancer cells
PTEN is a phosphatase that regulates the phosphatidylinositol-3 kinase signalling pathway and is inactivated in many tumour types. Heet al.show that a mannosidase, α-mannosidase 2C1, can inactivate PTEN in prostate cancer cells, and that PTEN-positive human prostate tumours overexpress α-mannosidase 2C1.
- Lizhi He
- , Catherine Fan
- & Damu Tang
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Article
| Open AccessRapid cell-surface prion protein conversion revealed using a novel cell system
The study of prion diseases has been hampered as there is no method to distinguish newly formed abnormal prion protein conformers. Here, the authors describe a method to study newly formed abnormal prion protein and demonstrate that it is produced within 1 minute of cell exposure to prions.
- R. Goold
- , S. Rabbanian
- & S.J. Tabrizi
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Article
| Open AccessRespiratory distress and perinatal lethality in Nedd4-2-deficient mice
In vitrostudies have suggested that the ubiquitin ligase, Nedd4-2, regulates several proteins, including the epithelial sodium channel. Here by examining Nedd4-2-deficient mice, the authors demonstrate that Nedd4-2 is essential for epithelial sodium channel regulation, fetal and postnatal lung function and animal survival.
- Natasha A. Boase
- , Grigori Y. Rychkov
- & Sharad Kumar
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Article
| Open AccessThe deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility
Deubiquitinating enzymes are involved in multiple cellular processes, including cell viability. The authors reveal a role for the deubiquitinating enzyme, USP17, in the migration of cells in response to chemokines and show that USP17 is required for the relocalization of GTPases involved in cell motility.
- Michelle de la Vega
- , Alyson A. Kelvin
- & James A. Johnston
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The acetylation of tau inhibits its function and promotes pathological tau aggregation
Phosphorylation of the microtubule-associated protein tau is associated with disease, but other post-translational modifications of tau are not well studied. Here, Cohenet al. study the acetylation of tau and suggest that this form of the protein may be associated with tauopathies.
- Todd J. Cohen
- , Jing L. Guo
- & Virginia M. Y. Lee
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Article
| Open AccessInflammation driven by tumour-specific Th1 cells protects against B-cell cancer
Inflammation can result in the formation of tumours, but the immune system is also involved in the elimination of cancer cells. Here, the authors show that inflammation driven by tumour-specific CD4+T cells results in tumour regression and identify a list of cytokines associated with cancer prevention.
- Ole Audun Werner Haabeth
- , Kristina Berg Lorvik
- & Alexandre Corthay
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Human TSC2-null fibroblast-like cells induce hair follicle neogenesis and hamartoma morphogenesis
Mutations inTSC2 lead to the formation of benign tumours called hamartomas. In this study, using a mouse xenograft model, the authors demonstrate that fibroblasts from patients carrying TSC2mutations can induce keratinocytes to form both hair follicles and hamartoma-like growths with active mTOR signalling.
- Shaowei Li
- , Rajesh L. Thangapazham
- & Thomas N. Darling
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Article
| Open AccessSoil clay content underlies prion infection odds
The infectious prion diseases affect numerous hoofed animal species, and it has been suggested that the properties of the local soil affect transmission of these diseases. Here, the authors studied two North American locations and demonstrate that soil clay content can influence the infection rate in deer.
- W. David Walter
- , Daniel P. Walsh
- & Michael W. Miller
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Article
| Open AccessGipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human
Progressive sensorineural hearing loss affects many people, but the underlying genetics remain largely undefined. Here, the authors identify mutations inGIPC3in mice and two consanguineous families that lead to hearing loss and in mice cause defects in the structure of stereocilia bundles and audiogenic seizures.
- Nikoletta Charizopoulou
- , Andrea Lelli
- & Konrad Noben-Trauth
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Article
| Open AccessThe Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice
Post-translational modifications are important in regulating protein function and turnover, and Ufm1 is part of a recently identified protein modification system. In this study, the authors show that Uba5, a component of the Ufm1 system, is important for regulating haematopoiesis and the differentiation of erythroid cells.
- Kanako Tatsumi
- , Harumi Yamamoto-Mukai
- & Masaaki Komatsu
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Article
| Open AccessProstaglandin E2 and SOCS1 have a role in intestinal immune tolerance
The gut is populated by a myriad of microorganisms and how the immune system tolerates their presence is of great interest. Here, by studying colon morphology in multiple knockout mice, the authors demonstrate a potential role for prostaglandin E2 and SOCS1 in mediating immune tolerance.
- Takatoshi Chinen
- , Kyoko Komai
- & Akihiko Yoshimura
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Article
| Open AccessChromatin remodelling complex dosage modulates transcription factor function in heart development
Inherited congenital heart defects are prevalent in the human population, but the molecular mechanisms are poorly understood. In this article, deficiency in the chromatin remodelling factor, Brg1, is shown to alter cardiac development in both mouse and zebrafish laboratory models.
- Jun K. Takeuchi
- , Xin Lou
- & Benoit G. Bruneau
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Article
| Open AccessPAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin
The activity of serine proteases, including CAP1/Prss8, is altered in some human skin disorders; however, the downstream effectors of these proteins are relatively unknown. Here, using animal models, the authors show that protease-activated receptor-2 is a critical component of the CAP1/Prss8 signalling cascade.
- Simona Frateschi
- , Eric Camerer
- & Edith Hummler
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Article
| Open AccessTumour-initiating stem-like cells in human prostate cancer exhibit increased NF-κB signalling
Tumours consist of heterogeneous cell types that respond differently to treatment. Here, on the basis of the expression of three different proteins, the authors describe a subset of prostate cancer cells that have stem cell-like properties that are able to initiate tumour formationin vivo.
- Vinagolu K. Rajasekhar
- , Lorenz Studer
- & Howard I. Scher
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Article
| Open AccessConformational rearrangement of gastric H+,K+-ATPase induced by an acid suppressant
The gastric proton pump, H+,K+-ATPase, contributes to stomach acidification and is a target of acid suppressants. Here, the three-dimensional structure of the pump is determined using electron crystallography, providing the first structural information about the binding of a new class of acid suppressants.
- Kazuhiro Abe
- , Kazutoshi Tani
- & Yoshinori Fujiyoshi
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Article
| Open AccessDisruption of TBP-2 ameliorates insulin sensitivity and secretion without affecting obesity
Thioredoxin binding protein-2 (TBP-2) mutant mice have abnormal insulin sensitivity and secretion. In this study, TBP-2-null obese mice are shown to have improved insulin sensitivity and glucose intolerance, suggesting a potential role for TBP-2 inhibition in diabetes treatment.
- Eiji Yoshihara
- , Shimpei Fujimoto
- & Hiroshi Masutani
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Article
| Open AccessGlobal distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis
Sixty years ago it was suggested that the sickle cell disease mutation survives because the heterozygous genotype confers resistance to malaria, resulting in correlation of the two geographical distributions. The authors use a new global assembly of sickle allele frequencies to support this hypothesis at the global scale.
- Frédéric B. Piel
- , Anand P. Patil
- & Simon I. Hay
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Article
| Open AccessTRPM7 is essential for Mg2+ homeostasis in mammals
Magnesium is an essential element of the diet and is a cofactor for many enzymes. In this study, the channel kinase TRPM7 is shown to be essential for magnesium homeostasis, and heterozygous mice lacking the kinase domain show a defect in absorption of magnesium from the diet.
- Lillia V. Ryazanova
- , Lusliany J. Rondon
- & Alexey G. Ryazanov
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Article
| Open AccessA β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain
Little is known about β-synuclein mutations in neurological disease. In this article, the authors demonstrate that mice with a mutation in β-synuclein show progressive neurodegenerative disease and suggest that this mutation can enhance the brain defects caused by α-synuclein mutations in mice.
- Masayo Fujita
- , Shuei Sugama
- & Makoto Hashimoto
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Article
| Open AccessA quantitative analysis of transmission efficiency versus intensity for malaria
Recent work has shown that the transmission of malaria from mosquito to human is inefficient. In this study, an analysis of published literature is used to understand this inefficiency, which is likely due to heterogeneous biting, where 20% of people receive 80% of the bites.
- David L. Smith
- , Chris J. Drakeley
- & Simon I. Hay
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Article
| Open AccessTectorial membrane travelling waves underlie abnormal hearing in Tectb mutant mice
Mutation of theTectbgene reduces auditory sensitivity but increases frequency selectivity. Here the authors show that Tectb mutation reduces both the spatial and temporal propagation of travelling waves along the tectorial membrane, explaining the unexpected auditory abnormalities in this mutant.
- Roozbeh Ghaffari
- , Alexander J. Aranyosi
- & Dennis M. Freeman
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Article
| Open AccessB-cell depletion reveals a role for antibodies in the control of chronic HIV-1 infection
HIV infection can be partially regulated by the host immune system; however whether B cells contribute to this response is unclear. Huanget al. show that transient depletion of B cells can result in an increase in HIV viral load suggesting that these immune cells do participate in the control of HIV infection.
- Kuan-Hsiang G. Huang
- , David Bonsall
- & Paul Klenerman
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Article
| Open AccessRapid calcium-dependent activation of Aurora-A kinase
Aurora-A kinase localizes to centrosomes, is involved in the progression through mitosis and is overexpressed in certain cancers. Here, calcium is shown to induce Aurora-A auto-phosphorylation in a calmodulin-dependent manner, suggesting a novel role for Aurora-A in non-mitotic cells.
- Olga V. Plotnikova
- , Elena N. Pugacheva
- & Erica A. Golemis
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Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes
Pseudogenes are prevalent in the human genome; however, their biological function is relatively unknown. In this study, the high mobility group A1 (HMGA1) pseudogene is shown to destabilizeHMGA1 mRNA. These findings have implications for diabetes, as two patients are reported to express high levels of the HMGA1pseudogene.
- Eusebio Chiefari
- , Stefania Iiritano
- & Antonio Brunetti
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Article
| Open AccessIdentification of high-quality cancer prognostic markers and metastasis network modules
There has been great interest in attempting to identify gene expression signatures that predict cancer survival. In this study a new algorithm is developed to analyse gene expression datasets that accurately classify both ER+ and ER− breast cancers into low- and high-risk groups.
- Jie Li
- , Anne E.G. Lenferink
- & Edwin Wang
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Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer
Ageing associated diseases are the subject of intense study. In this article Serrano and colleagues demonstrate that Sirt1 over-expression in mice prevents both ageing associated diseases and liver cancer.
- Daniel Herranz
- , Maribel Muñoz-Martin
- & Manuel Serrano
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