Featured
-
-
Article |
YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer
Prostate cancer is regulated by androgen receptor signalling; however, progressive disease can also be androgen-independent, thus hindering antiandrogen therapy. Here, interaction of the Hippo pathway protein, YAP1, with the androgen receptor is shown to confer castration-resistant prostate cancer.
- Gamze Kuser-Abali
- , Ahmet Alptekin
- & Bekir Cinar
-
Article
| Open AccessRhomboid domain containing 1 promotes colorectal cancer growth through activation of the EGFR signalling pathway
Rhomboid proteins are involved in human cancer progression. Here, the authors show that RHBDD1, a rhomboid intramembrane serine protease, promotes tumor growth in colorectal cancer via cleavage and secretion of TGFα, and activation of the EGFR/Raf/MEK/ERK signalling pathway.
- Wei Song
- , Wenjie Liu
- & Linfang Wang
-
Article |
Association analysis identifies new risk loci for congenital heart disease in Chinese populations
Genome-wide association studies in Chinese and Europeans have identified multiple loci associated with congenital heart disease. Here the authors use existing GWAS data to conduct an extended three-stage analysis in Han Chinese and identify four novel loci linked to disease risk in this population.
- Yuan Lin
- , Xuejiang Guo
- & Zhibin Hu
-
Article
| Open AccessGenome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations
Polycystic Ovary Sydrome is a highly heritable, complex reproductive disorder with unknown underlying genetic factors. Here Hayes and Urbanek et al. identify three loci in European women strongly associated with neuroendocrine changes and disease susceptibility.
- M. Geoffrey Hayes
- , Margrit Urbanek
- & Andrea Dunaif
-
Article
| Open AccessBreaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology
Immunosuppression has been unsuccessful in treatment of Alzheimer’s disease. Here the authors show in a mouse model of the disease that transient inhibition of regulatory T cells mitigates amyloid plaque pathology and reverses cognitive decline, whereas augmenting these cells worsens the pathology.
- Kuti Baruch
- , Neta Rosenzweig
- & Michal Schwartz
-
Article
| Open AccessGenome-wide analysis of the genetic regulation of gene expression in human neutrophils
Neutrophils are abundant immune cells important for antimicrobial defence and in autoimmunity. Here, by mapping expression quantitative trait loci (eQTL) in neutrophils of Chinese ethnicity from Singapore, Andiappan et al.provide a resource for understanding immune-related trait associated genetic variants.
- Anand Kumar Andiappan
- , Rossella Melchiotti
- & Olaf Rotzschke
-
Article |
Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling
Targetting tumour angiogenesis is a useful strategy to reduce tumour burden; however, the clinical benefits of anti-angiogenetic drugs are modest. Here, the authors show that HGFR signalling, which contributes to tumour angiogenesis, requires Arf6 and that blocking Arf6 can lead to reduced tumour growth in mice.
- Tsunaki Hongu
- , Yuji Funakoshi
- & Yasunori Kanaho
-
Article
| Open AccessTruncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers
Some colon carcinomas with microsatellite instability carry a frameshift mutation in a tumour suppressor UVRAG. Here the authors show that mutant UVRAG triggers colorectal cancer by antagonizing the activity of normal UVRAG in autophagy and chromosomal stability, but also sensitizes the cancer to DNA damage-inducing chemotherapeutic drugs.
- Shanshan He
- , Zhen Zhao
- & Chengyu Liang
-
Article
| Open AccessMutations in CDCA7 and HELLS cause immunodeficiency–centromeric instability–facial anomalies syndrome
Immunodeficiency-centromeric instability-facial anomalies syndrome is a life threatening autosomal recessive disorder caused by mutations in DNMT3B and ZBTB24. Here Thijssen et al. identify mutations in CDCA7 and HELLSin previously unexplained cases.
- Peter E. Thijssen
- , Yuya Ito
- & Hiroyuki Sasaki
-
Article
| Open AccessDOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression
DOT1L is an anti-cancer therapeutic target in leukaemia but has a poorly understood role in solid tumours. Here the authors show that DOT1L expression is associated with poor survival and aggressive cancers by helping to epigenetically activate the epithelial-mesenchymal transition during breast cancer progression.
- Min-Hyung Cho
- , Ji-Hye Park
- & Gu Kong
-
Article
| Open AccessPI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis
Mutations and post-translational modifications of the PI3K/AKT pathway inhibitor PTEN are a feature of many cancers, but these have not been associated with cervical cancer. Here, the authors identify a PI3K/AKT-mediated ubiquitination degradation pathway of PTEN that occurs in patients with cervical cancer.
- Min-Sik Lee
- , Man-Hyung Jeong
- & Jaewhan Song
-
Article |
Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from γδ-T cells
Adiponectin levels are decreased in metabolic syndrome and psoriasis patients. Here the authors show that adiponectin suppresses the pathogenic production of IL-17 of γδ T cells, and adiponectin administration improves psoriasis-like symptoms in a mouse model of the disease.
- Sayaka Shibata
- , Yayoi Tada
- & Shinichi Sato
-
Article
| Open AccessGenome-wide burden of deleterious coding variants increased in schizophrenia
Schizophrenia is a complex disorder with high heritability but poorly understood genetics. Here Olde Loohuis et al.compare schizophrenia patients to unaffected individuals and identify an increased individual burden of rare deleterious mutations in patients.
- Loes M. Olde Loohuis
- , Jacob A. S. Vorstman
- & Roel A. Ophoff
-
Article
| Open AccessCrucial roles of RSK in cell motility by catalysing serine phosphorylation of EphA2
The EphA2 receptor tyrosine kinase is overexpressed in many cancers and is reported to be phosphorylated by Akt. Here, Zhou et al.show that RSK, rather than Akt, phosphorylates EphA2 on Ser-897, and this regulates cell migration and invasion of metastatic cancer cells.
- Yue Zhou
- , Naoki Yamada
- & Hiroaki Sakurai
-
Article
| Open AccessRecessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III
Some RNA polymerase (POLR) 3-related leukodystrophy cases do not have the causal mutations in POLR3A and POLR3B. Here, by exome sequencing, the authors identify recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, impairing assembly and nuclear import of POLR3, but not POLR1.
- Isabelle Thiffault
- , Nicole I. Wolf
- & Geneviève Bernard
-
Article
| Open AccessGenomic modulators of gene expression in human neutrophils
Neutrophils are the most abundant subset of leukocyte and central to many diseases. Here by mapping expression quantitative trait loci (eQTL) in the context of epigenetic marks in neutrophils and monocytes of 101 healthy European adults, the authors provide a resource to advance understanding of immune-related trait-associated genetic variants.
- Vivek Naranbhai
- , Benjamin P. Fairfax
- & Julian C. Knight
-
Article
| Open AccessIntegrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma
Rhabdomyosarcoma is a common childhood soft-tissue cancer. Here Seki and Nishimura analyse the exome, transcriptome, copy number and DNA methylome of 60 sarcomas and identify distinct methylation subgroups associated with genetic and clinical features.
- Masafumi Seki
- , Riki Nishimura
- & Junko Takita
-
Article
| Open AccessDisruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E-deficient mice
Atherogenesis involves coordinated action of different cell types and factors. Here the authors show that the kinase Pak1 represents a key pro-atherogenic factor affecting the function of macrophages and vascular smooth muscle cells, including their production of proinflammatory cytokine IL-6 and chemokine MCP-1, and retention of cholesterol.
- Nikhlesh K. Singh
- , Sivareddy Kotla
- & Gadiparthi N. Rao
-
Article
| Open AccessGrb2 monomer–dimer equilibrium determines normal versus oncogenic function
Grb2 is an adaptor protein that can exist as a dimer that dissociates on phosphorylation of Y160. Here, the authors show that only the monomeric protein is capable of activating mitogen-activated protein kinase signal transduction and hence control oncogenic outcome.
- Zamal Ahmed
- , Zahra Timsah
- & John E. Ladbury
-
Article
| Open AccessInherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children
Genome-wide association studies indicate a strong genetic susceptibility to acute lymphoblastic leukaemia in children, though the effect on protein-coding genes is not fully understood. Here Xu and Zhang et al. identify a missense variant in CDKN2Awhich reduces tumour suppression.
- Heng Xu
- , Hui Zhang
- & Jun J. Yang
-
Article |
β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling
Hepatocellular carcinoma can arise from hepatitis as a consequence of persistent inflammation. Here, Yang et al.show that the protein G-protein-coupled receptor adaptor β-arrestin1 promotes hepatocellular carcinogenesis through pro-inflammatory Akt signalling.
- Yidong Yang
- , Yunwei Guo
- & Bin Wu
-
Article
| Open AccessParkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation
ß-Sheet-rich aggregates of α-synuclein (αS) characterize Parkinson's disease (PD) and recent work suggests that αS exists as α-helix-rich tetramers and related low-nmultimers in normal cells. Here the authors show that αS mutations associated with familial PD decrease the intraneuronal tetramer:monomer ratio and are correlated with neurotoxicity.
- Ulf Dettmer
- , Andrew J. Newman
- & Dennis Selkoe
-
Article
| Open AccessGenome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy
Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.
- Naomi Kouri
- , Owen A. Ross
- & Dennis W. Dickson
-
Article |
Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities
Mutations in the tumour suppressor p53 can produce a protein that has additional functions. Here, the authors describe gain of function mutants of p53 that induce the expression of genes involved in nucleotide metabolism, which increases the activity of GTPases and results in invasion and metastasis.
- Madhusudhan Kollareddy
- , Elizabeth Dimitrova
- & Luis A. Martinez
-
Article
| Open AccessDe novo mutations in PLXND1 and REV3L cause Möbius syndrome
lt has been debated for decades if there is a genetic aetiology underlying Möbius syndrome, a neurological disorder characterized by facial paralysis. Here Tomas-Roca et al. use exome sequencing and identify de novo mutations in PLXND1 and REV3L, representing converging pathways in hindbrain development.
- Laura Tomas-Roca
- , Anastasia Tsaalbi-Shtylik
- & Hans van Bokhoven
-
Article |
Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons
Abnormal accumulation of TDP-43 and FUS proteins is found in a neurodegenerative disease amyotrophic lateral sclerosis. Here the authors show by modelling the disease in worms that these proteins activate local and distal immune responses, and blocking this pathway in neurons ameliorates the disease.
- Julie Vérièpe
- , Lucresse Fossouo
- & J Alex Parker
-
Article
| Open AccessSite-specific processing of Ras and Rap1 Switch I by a MARTX toxin effector domain
V. vulnificus, a bacteria that cause life-threatening septicaemia following wound infections or tainted food consumption, utilizes MARTX toxins for toxic effector delivery. Here the authors show that the MARTX virulence factor DUF5 targets the cellular MAP kinase pathway as a Ras and Rap1 site-specific protease.
- Irena Antic
- , Marco Biancucci
- & Karla J. F. Satchell
-
Article
| Open AccessTCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport
Severe congenital development defects such as Jeune syndrome can result from the malfunction of primary cilia and dynein. Here Schmidts et al. report unique biallelic null mutations in a gene encoding a dynein light chain, helping to explain the nature of ciliopathies in human patients.
- Miriam Schmidts
- , Yuqing Hou
- & Hou-Feng Zheng
-
Article |
Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression
AF6, an essential protein for the organization of cell-to-cell junctions and development, is aberrantly expressed in several tumors but its role in pancreatic cancer is not clear. Here the authors show that in pancreatic cancer, loss of AF6 expression leads to induction of the EMT transcription factor Snail.
- Yi Xu
- , Renxu Chang
- & Lixing Zhan
-
Article
| Open AccessAcetylation of Beclin 1 inhibits autophagosome maturation and promotes tumour growth
Beclin 1 is an essential autophagy effector, necessary to form the autophagosome. Here Sun et al. show that Beclin 1 acetylation regulated by p300 and SIRT1 inhibits autophagosome maturation, and mutation of the acetylation sites leads to tumour growth suppression in vivo.
- Ting Sun
- , Xuan Li
- & Xiao-Feng Zhu
-
Article
| Open AccessMajor histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1
Ankylosing spondylitis is a common, highly inheritable inflammatory arthritis with poorly understood biology. Here Brown, Cortes and colleagues use fine mapping of the major histocompatibility complex and identify novel associations, and identify other HLA alleles that like HLA-B27 interact with ERAP1 variants to influence disease risk.
- Adrian Cortes
- , Sara L. Pulit
- & Matthew A. Brown
-
Article
| Open AccessGenome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese
Raised serum urate levels are a risk factor for gout, a common form of inflammatory arthritis. Here Li et al.conduct a multistage genome-wide association study in a Han Chinese population and identify three novel loci likely associated with the progression from hyperuricemia to gout.
- Changgui Li
- , Zhiqiang Li
- & Yongyong Shi
-
Article
| Open AccessCD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis
Dendritic cells are critical for initiation of immune responses and for induction of tolerance. Here the authors show that deletion of survival factor c-flip in CD11c-expressing cells subset perturbs CD8a+dendritic cell, NK and macrophage pools, and leads to development of autoimmune arthritis.
- Qi-Quan Huang
- , Harris Perlman
- & Richard M. Pope
-
Article |
IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis
Innate immune responses are regulated in the intestine to prevent excessive inflammation. Here the authors demonstrate a pivotal role for intestinal macrophages that constitutively produce IL-10 in controlling excessive innate immune activation and preventing tissue damage after an acute bacterial infection.
- Petra Krause
- , Venetia Morris
- & Masako Murai
-
Article |
Two susceptibility loci identified for prostate cancer aggressiveness
Prostate cancer often does not progress to invasive disease and thus markers predicting the course of the disease progression are critical for optimal treatment choices. Here the authors show that variants at two genetic loci correlate with the aggressiveness of prostate cancer.
- Sonja I. Berndt
- , Zhaoming Wang
- & Stephen J. Chanock
-
Article |
Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis
Autoantibodies targeting citrunillated proteins are common in rheumatoid arthritis patients. Here the authors show that vinculin (a human protein) and some microbial proteins are recognized by these antibodies and by CD4+T cells, and this response is absent in patients carrying a protective HLA allele.
- Jurgen van Heemst
- , Diahann T. S. L. Jansen
- & René E. Toes
-
Article
| Open AccessAcetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer
Folate plays an essential role in dividing cells and is regulated by methionine adenosyltransferase (MAT), where a switch from MAT Iα to MAT IIα expression seems to promote liver cancer progression. Here the authors demonstrate that MAT IIα stability is regulated by acetylation and this regulation is important for tumour growth.
- Hong-Bin Yang
- , Ying-Ying Xu
- & Qun-Ying Lei
-
Article |
Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes
Historically, Mendelian disorders were used to provide the first insight into cancer-associated genes. Here Melamed et al.use the unprecedented scope of electronic health records to explore genetic relationships and uncover potentially new drivers of cancer.
- Rachel D. Melamed
- , Kevin J. Emmett
- & Raul Rabadan
-
Article
| Open AccessCorrection of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy
Phospholamban (PLN) is a regulator of heart contractility. Here the authors show that cardiomyocytes derived from induced pluripotent stem cells of a cardiomyopathy patient with mutant PLN exhibit functional defects consistent with the disease, and that this mutation can be functionally corrected by genome editing and gene therapy.
- Ioannis Karakikes
- , Francesca Stillitano
- & Roger J. Hajjar
-
Article |
Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma
Aortic dissection and intramural haematoma are caused by separation of the aortic wall via an unknown mechanism. Here the authors show that the inflammatory cytokine, granulocyte macrophage colony-stimulating factor, is a central regulatory molecule causative of these conditions in mice and humans.
- Bo-Kyung Son
- , Daigo Sawaki
- & Toru Suzuki
-
Article
| Open AccessId1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation
Tumour progression is promoted by the generation of an immunosuppressive macroenvironment. Here, the authors demonstrate that the Inhibitor of Differentiation 1 promotes the switch from dendritic cell differentiation towards myeloid-derived suppressor cell expansion during tumour progression.
- Marianna Papaspyridonos
- , Irina Matei
- & David Lyden
-
Article |
Crystalline silica-induced leukotriene B4-dependent inflammation promotes lung tumour growth
Chronic exposure to silica crystals can cause lung inflammation and cancer. Here, the authors show that mast cells and macrophages respond to silica crystals by producing leukotriene B4, which recruits neutrophils leading to inflammation, and that blocking this pathway attenuates cancer progression.
- Shuchismita R. Satpathy
- , Venkatakrishna R. Jala
- & Bodduluri Haribabu
-
Article |
REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway
REGγ, a proteasome activator, is associated with multiple oncogenic pathways in human cancers and can promote the degradation of multiple proteins including p53. Here the authors highlight a potential role for REGγ in skin cancer and propose a molecular mechanism linking p38 MAPK and Wnt signalling.
- Lei Li
- , Yongyan Dang
- & Xiaotao Li
-
Article |
Enterobacteria-secreted particles induce production of exosome-like S1P-containing particles by intestinal epithelium to drive Th17-mediated tumorigenesis
Microbial and host cells in the gut exchange complex signals that we only begin to decipher. Here the authors show that pathogenic but not commensal gut bacteria secrete microparticles, which in turn induce changes in the content of the mucosa-produced exosomes to promote Th17-mediated tumorigenesis.
- Zhongbin Deng
- , Jingyao Mu
- & Huang-Ge Zhang
-
Article |
DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis
DNA methyltransferase1 (DNMT1) plays a key role in stem cell and progenitor cell maintenance in mammalian epithelium tissues. Here the authors uncover a role for DNMT1 in the regulation of stem/progenitor cells in normal and tumorigenic mouse mammary gland.
- Rajneesh Pathania
- , Sabarish Ramachandran
- & Muthusamy Thangaraju
-
Article
| Open AccessGenome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility
Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here Yin et al. conduct a large trans-ethnic genome-wide meta-analysis and identify novel loci that contribute to population-specific susceptibility.
- Xianyong Yin
- , Hui Qi Low
- & Jianjun Liu
-
Article |
APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma
Rearrangements of the Ig loci are essential for generating antibody diversity but abnormal translocations can be a driving event for myeloma. Here Walker et al. perform whole exome sequencing on myeloma patients to capture the diversity of mutational changes.
- Brian A. Walker
- , Christopher P. Wardell
- & Gareth J. Morgan
-
Article
| Open AccessEpigenomic evolution in diffuse large B-cell lymphomas
The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. Here the authors characterize epigenetic evolution in aggressive B-cell lymphoma and find that epigenomic heterogeneity may not only support and drive the relapse phenotype but also be used to predict lymphoma relapse.
- Heng Pan
- , Yanwen Jiang
- & Olivier Elemento
-
Article |
ATM kinase sustains HER2 tumorigenicity in breast cancer
ATM is a tumour suppressor activated in response to DNA damage. Here, the authors unveil a new tumour-promoting role for ATM in HER2-driven breast cancers, and show that ATM stimulates the interaction between HER2 and HSP90, therefore preventing HER2 from degradation.
- Venturina Stagni
- , Isabella Manni
- & Daniela Barilà