Diseases

  • Article |

    The processes that regulate melanoblast migration during development are also thought to be involved in melanoma metastasis. Here, Prex1 null mice are shown to have a melanoblast migration defect and, when crossed to a mouse model of melanoma, are resistant to metastasis, suggesting a role for Prex1 in metastatic melanoma.

    • Colin R. Lindsay
    • , Samuel Lawn
    •  & Owen J. Sansom
  • Article |

    Erythropoietin circulates in the blood and is essential for erythropoiesis but its role in metabolic homeostasis has not been examined. Tenget al. show that when the erythropoietin receptor is only expressed in erthyroid cells, mice develop obesity and insulin resistance, suggesting that the receptor has a key role in fat mass accumulation.

    • Ruifeng Teng
    • , Oksana Gavrilova
    •  & Constance Tom Noguchi
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article |

    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
  • Article |

    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
  • Article
    | Open Access

    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
  • Article |

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article |

    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
  • Article |

    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
  • Article |

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article |

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article |

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article |

    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
  • Article
    | Open Access

    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