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| Open AccessMacrophage ABHD5 promotes colorectal cancer growth by suppressing spermidine production by SRM
ABHD5 is a co-activator of lipolysis. Here the authors show that in tumour-associated macrophages ABHD5 inhibits ROS-dependent induction of C/EBPɛ, which transcriptionally activates spermidine synthase, and that blocking ABHD5 delays colorectal cancer growth in mice by inhibiting spermidine production.
- Hongming Miao
- , Juanjuan Ou
- & Houjie Liang
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Article
| Open AccessERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation
It is unclear how the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways interact with other signals in intestinal epithelial cells. Here, the authors show that upon loss of Erk1/2, or pharmacological inhibition of MEK1/2, the ERK5 pathway is upregulated to maintain epithelial cell proliferation.
- Petrus R. de Jong
- , Koji Taniguchi
- & Eyal Raz
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Article
| Open AccessTumour resistance in induced pluripotent stem cells derived from naked mole-rats
The naked mole-rat exhibits an exceptional resistance to cancer. Here, the authors show that induced pluripotent stem cells derived from the naked mole-rat lack teratoma-forming tumorigenicity due to a naked mole-rat-specific ARF-dependent tumour-suppression mechanism.
- Shingo Miyawaki
- , Yoshimi Kawamura
- & Kyoko Miura
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Article
| Open AccessAltered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism
SHANK3 mutations have been linked to autism spectrum disorders, although the underlying mechanisms remain unclear. Here, the authors generate a complete knockout Shank3 mouse model, identifying ASD-like behaviours associated with impaired mGluR5-Homer scaffolding and abnormal brain connectivity.
- Xiaoming Wang
- , Alexandra L. Bey
- & Yong-hui Jiang
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Article
| Open AccessDNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells
De novoDNA methylation is carried out by DNA methyltransferase DNMT3A/B, although DNMT3B isoforms without active catalytic domains are widely expressed. Here, the authors show that DNMT3B isoforms stimulate gene body methylation and re-methylation independently of the isoforms' catalytic activity.
- Christopher E. Duymich
- , Jessica Charlet
- & Gangning Liang
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Article
| Open AccessAirway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency
The mechanisms driving lung inflammation and remodelling in chronic obstructive pulmonary disease (COPD) are incompletely understood. Here the authors show that lack of secretory IgA promotes bacterial invasion in small airways, resulting in leukocyte recruitment and a COPD-like phenotype.
- Bradley W. Richmond
- , Robert M. Brucker
- & Vasiliy V. Polosukhin
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Article
| Open AccessSialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis
Post-translational modifications, such as glycosylation and sialylation, are thought to confer disease modifying effects on autoimmune-associated antibodies, including anti-citrullinated protein antibodies in rheumatoid arthritis. Here the authors show that sialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis in mice.
- Yuhsuke Ohmi
- , Wataru Ise
- & Koichi Furukawa
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Article
| Open AccessCD8+ T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing
Rasmussen Encephalitis is a rare neurological disease accompanied by inflammation and T cell infiltration in the brain. Here the authors show that the severity of this disease correlates with clonal CD8 T cell expansion.
- Tilman Schneider-Hohendorf
- , Hema Mohan
- & Nicholas Schwab
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Article
| Open AccessZyxin-Siah2–Lats2 axis mediates cooperation between Hippo and TGF-β signalling pathways
Hippo and TGF-β are crucial signalling pathways involved in the development of various types of tumours. Here, the authors demonstrate that TGF-β can directly regulate Hippo pathway through the stabilization of the scaffold protein Zyxin, which forms a ternary complex with Siah2 and Lats2 promoting Lats2 degradation and YAP activation.
- Biao Ma
- , Hongcheng Cheng
- & Yushan Zhu
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Article
| Open AccessCoagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis
It is unclear whether cancer-related hypercoagulation and neutrophilia contribute to tumorigenesis. In this study, the authors find that activation of the complement cascade causes hypercoagulation that leads to polarization of neutrophils in a mouse model of intestinal cancer, and show that blocking complement activation can reduce tumour formation.
- Silvia Guglietta
- , Andrea Chiavelli
- & Maria Rescigno
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Article
| Open AccessIncreased amyloidogenic APP processing in APOE ɛ4-negative individuals with cerebral β-amyloidosis
Autosomal dominant Alzheimer's disease is thought to be caused by increased amyloidogenic APP processing. Mattson et al.show that association between brain Aβ and cerobrospinal fluid Aβ40 levels is stronger in APOE ɛ4 negative people, suggesting that increased processing may also underlie sporadic disease.
- Niklas Mattsson
- , Philip S. Insel
- & Oskar Hansson
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Article
| Open AccessPolycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network
Polycomb-mediated gene regulation has been implicated in gliomas. Here the authors integrate transcriptomic and epigenomic analyses to define Polycomb-dependent networks that promote gliomagenesis, and find that the Polycomb-dependent silencing of the transcription factor Zfp423hinders survival.
- Elena Signaroldi
- , Pasquale Laise
- & Giuseppe Testa
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Article
| Open AccessFAT1 mutations cause a glomerulotubular nephropathy
Steroid-sensitive nephrotic syndrome (SRNS) can cause CKD and necessitate kidney transplant. Here the authors identify FAT1 mutations by homozygosity mapping and whole-exome sequencing in families with SRNS and provide functional mouse and zebrafish evidence that FAT1 is required for normal glomerular and tubular function and that FAT1 mutations can cause SRNS.
- Heon Yung Gee
- , Carolin E. Sadowski
- & Friedhelm Hildebrandt
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| Open AccessA monoclonal antibody against KCNK9 K+ channel extracellular domain inhibits tumour growth and metastasis
The potassium channel KCNK9 mediates important biological processes and is often overexpressed in breast and lung cancers. In this study, the authors developed a specific monoclonal antibody against the extracellular domain of KCNK9 and show that it inhibits cancer growth and metastasis in vivothrough both cell autonomous and immune-dependent cellular cytotoxicity.
- Han Sun
- , Liqun Luo
- & Min Li
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Article
| Open AccessC1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation
C1q is known to initiate the activation of the complement classical pathway. Here, the authors show the C1q is expressed in the tumour microenvironment and can promote cancer cell migration and adhesion in a complement activation-independent manner.
- Roberta Bulla
- , Claudio Tripodo
- & Francesco Tedesco
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Article
| Open AccessDefective DNA single-strand break repair is responsible for senescence and neoplastic escape of epithelial cells
It is recognized that cellular senescence is triggered by DNA damage as a protective mechanism against tumorigenesis. Here the authors show that DNA single-strand breaks of oxidative origin can induce a transient senescent state followed by the emergence of clonal transformed cells.
- Joe Nassour
- , Sébastien Martien
- & Corinne Abbadie
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Article
| Open AccessDNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer
Altered epigenetics is a feature of cancer but whether these changes occur early in tumour development is unclear. Here, the authors analyse methylation events in breast cancer and adjacent normal pairs, and show that methylation changes in the normal tissue are also found in the tumour, suggesting that some of these events occur early in cancer.
- Andrew E Teschendorff
- , Yang Gao
- & Martin Widschwendter
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Article
| Open AccessThe occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation
SMARCB1 inactivation is prevalent in human atypical teratoid/rhabdoid tumours but a mouse model that accurately phenocopies the human disease is lacking. Here, the authors show that inactivation of SMARCB1between E6 and E10 in mice results in tumours that better recapitulate the human phenotype, compared to previously reported models.
- Zhi-Yan Han
- , Wilfrid Richer
- & Franck Bourdeaut
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Article
| Open AccessPeriprostatic adipocytes act as a driving force for prostate cancer progression in obesity
Obesity is associated with an elevated risk of prostate cancer. Here, the authors show that periprostatic adipose tissue promotes the migration and local invasion of prostate cancer cells by secreting the chemokine, CCL7, and that this process is enhanced in the context of obesity.
- Victor Laurent
- , Adrien Guérard
- & Catherine Muller
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Article
| Open AccessBPTF is required for c-MYC transcriptional activity and in vivo tumorigenesis
c-MYC genomic distribution is dictated by the epigenetic context but the mechanisms are unknown. Here, the authors show that c-MYC requires the chromatin reader BPTF to activate its transcriptional program and promote tumour development in vivo, suggesting that BPTF is a potential target for cancer therapy.
- Laia Richart
- , Enrique Carrillo-de Santa Pau
- & Francisco X. Real
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Article
| Open AccessNSD1 mutations generate a genome-wide DNA methylation signature
Sotos syndrome is an growth syndrome characterized by advanced growth in childhood, characteristic facial appearance and intellectual disability. Here the authors identify a genome-wide DNA methylation signature that accurately diagnoses Sotos Syndrome and distinguishes it from similar conditions.
- S. Choufani
- , C. Cytrynbaum
- & R. Weksberg
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| Open AccessAccumulation of differentiating intestinal stem cell progenies drives tumorigenesis
Intestinal homeostasis is ensured by stem cell self-renewal and differentiation while alterations of these processes can lead to cancer. In this study, using Drosophilagenetics the authors demonstrate that the loss of the transcription factor Sox21a blocks the differentiation of the intestinal stem cell progeny, which accumulate and form aggressive tumours.
- Zongzhao Zhai
- , Shu Kondo
- & Bruno Lemaitre
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Article
| Open AccessA novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51
Fanconi anaemia is an inherited disorder characterised by developmental abnormalities, bone marrow failure and predisposition to cancer. Here the authors report a de novo mutation in the DNA repair gene Rad51in an atypical subtype of Fanconi anaemia.
- Najim Ameziane
- , Patrick May
- & Josephine C. Dorsman
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| Open AccessSF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with diverse phenotypes and can derive from hematopietic stem cells after the acquisition of specific somatic aberrations. In this study, the authors show that MDS initiating cells in some cases of sideroblastic anemia with SF3B1 mutations, can arise from hematopoietic stem cells.
- Syed A. Mian
- , Kevin Rouault-Pierre
- & Ghulam J. Mufti
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| Open AccessRecruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression
E2F transcription factors are primarily known for the regulation of the cell cycle and are often dysregulated in cancer. Here, the authors show that during cancer progression E2F1 recruits a Pontin/Reptin complex to E2F target genes to open chromatin and increase E2F transcriptional response.
- Amy Tarangelo
- , Nathanael Lo
- & Patrick Viatour
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Article
| Open AccessInhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis
Aberrant Ras signalling resulting in downstream Mek/Erk pathway activation is found in many cancers. Here, the authors show that the phosphatase SHP2 dephosphorylates Ras resulting in increased Ras activity, and that increased SHP2 activity is found in glioblastomas.
- Severa Bunda
- , Kelly Burrell
- & Michael Ohh
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Saturated fatty acids regulate retinoic acid signalling and suppress tumorigenesis by targeting fatty acid-binding protein 5
Long chain fatty acids can influence the growth of cancer cells but the mechanisms involved are unclear. Here, the authors show that both saturated and unsaturated long chain fatty acids can influence retinoic acid signalling and suppress tumour growth in mice.
- Liraz Levi
- , Zeneng Wang
- & Noa Noy
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Article
| Open AccessAF4 uses the SL1 components of RNAP1 machinery to initiate MLL fusion- and AEP-dependent transcription
Protein fusions between MLL and AEP (AF4 family/ENL family/P-TEFb) constitutively activate their target genes to immortalize hematopoietic progenitors. Here, Okuda et al. show that MLL-AEP binds SL1, a component of the pre-initiation complex of RNA polymerase (RNAP) I, to initiate RNAP II dependent transcription.
- Hiroshi Okuda
- , Akinori Kanai
- & Akihiko Yokoyama
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| Open AccessRecurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney
The genetic basis of clear cell sarcomas of the kidney is not well understood. In this study, Roy et al. perform whole-exome and RNA sequencing of these tumours and identify recurrent internal tandem duplications in BCOR, a key constituent of a variant polycomb repressive complex.
- Angshumoy Roy
- , Vijetha Kumar
- & D. Williams Parsons
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| Open AccessmiR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth
The synergism between c-MYC and miR-17-19b plays an important role in lymphoma initiation. In this study, the authors identify a panel of targets co-regulated by miR-17-19b and in MYC-driven lymphoma and unravel the molecular mechanism through which miR-17-19b inhibits MYCtranslation.
- Marija Mihailovich
- , Michael Bremang
- & Tiziana Bonaldi
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Article
| Open AccessDelta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease
Age is the greatest risk factor for Alzheimer’s disease, yet how ageing regulates disease pathology is unclear. Here, the authors find that asparagine endopeptidase expression increases with age and cleaves APP, contributing to ß-amyloid production and cognitive defects in a transgenic mouse model.
- Zhentao Zhang
- , Mingke Song
- & Keqiang Ye
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Article
| Open AccessMeta-analysis identifies seven susceptibility loci involved in the atopic march
The development of asthma following eczema is known as the atopic march. Here the authors conduct a GWAS on affected children and identify two novel loci associated with the disease phenotype.
- Ingo Marenholz
- , Jorge Esparza-Gordillo
- & Young Ae Lee
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Article
| Open AccessBAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages
BAG3 is found in the serum of pancreatic cancer patients and can be used as a marker of disease, but its role in cancer is unclear. Here, the authors show that BAG3 secreted from tumour cells binds to and activates macrophages, which in turn promotes cell growth, and an antibody blocking BAG3 binding reduces tumour formation in mice.
- Alessandra Rosati
- , Anna Basile
- & Maria Caterina Turco
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Article
| Open AccessGut mucosal microbiome across stages of colorectal carcinogenesis
Changes in gut microbial communities contribute to the development of colorectal cancer. Here, the authors analyse the gut mucosal microbiome of patients and healthy subjects and identify distinct microbial consortia associated with different stages of colorectal cancer tumorigenesis.
- Geicho Nakatsu
- , Xiangchun Li
- & Joseph J. Y. Sung
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Article
| Open AccessPOH1 deubiquitylates and stabilizes E2F1 to promote tumour formation
The transcription factor E2F1 controls the expression of multiple genes and is frequently overactivated in cancer. Here, the authors show that E2F1 is deubiquitinated by POH1 and that this enhances the role of E2F1 in cell survival, and contributes to the pathogenesis of liver cancer.
- Boshi Wang
- , Aihui Ma
- & Yongzhong Liu
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Article
| Open AccessZinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1
Temporal lobe epilepsy can cause ionic imbalance in the brain and alter transcriptional activities. Here, van Loo et al.show that the increase in neuronal zinc following status epilepticus can induce transcriptional change via metal-regulatory transcription factor 1, and alter voltage-gated calcium channel CaV3.2 and intrinsic neuronal excitability.
- Karen M. J. van Loo
- , Christina Schaub
- & Albert J. Becker
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Article
| Open AccessAn LSC epigenetic signature is largely mutation independent and implicates the HOXA cluster in AML pathogenesis
Leukaemic stem cells are prevalent in acute myeloid leukemia. Here, Jung and colleagues derive a signature of 71 methylated genes that characterise these stem cells and find multiple HOXAgenes within the signature.
- Namyoung Jung
- , Bo Dai
- & Andrew P. Feinberg
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Article
| Open AccessModel of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells
With no cell lines available, investigating the aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs) has proved problematic. Here, Oikawa et al. establish a model of hFL-HCCs as a transplantable tumour line maintained in immune-compromised mice, which proves rich in cancer stem cells.
- Tsunekazu Oikawa
- , Eliane Wauthier
- & Lola M. Reid
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Article
| Open AccessLoss of KLF14 triggers centrosome amplification and tumorigenesis
Centrosome amplification is common in cancer, but the mechanism is not clear. Here the authors uncover a role for Kruppel-like factor 14 (KLF14) as a transcriptional repressor of polo-like kinase 4 (PLK4); KLF14 depletion correlates with increased PLK4 in human samples and leads to centrosome amplification and tumorigenesis in mice.
- Guangjian Fan
- , Lianhui Sun
- & Chuangui Wang
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Article
| Open AccessThe DNA structure and sequence preferences of WRN underlie its function in telomeric recombination events
The loss of WRN helicase leads to abnormalities at chromosome ends and is associated with premature ageing phenotypes characteristic of Werner syndrome. Here the authors show that WRN acts in a structure- and sequence-specific manner on recombination intermediates relevant to telomere maintenance.
- Deanna N. Edwards
- , Amrita Machwe
- & David K. Orren
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Article |
TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression
The epigenetic mark 5-hmC alters gene expression and is known to be regulated by TET proteins. Here, the authors show that 5-hmC and TET2 are reduced in prostate cancer via androgen receptor-dependent miRNA expression and are inversely correlated with prognosis.
- Ken-ichi Takayama
- , Aya Misawa
- & Satoshi Inoue
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Article
| Open AccessHIV–tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling
Some patients with HIV-associated tuberculosis develop an immune reconstitution inflammatory syndrome (TB-IRIS) in response to antiretroviral therapy. Here the authors identify genes differentially expressed in patients likely to progress to TB-IRIS and find activation of Toll-like receptor and inflammasome pathways.
- Rachel P. J. Lai
- , Graeme Meintjes
- & Robert J. Wilkinson
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Article
| Open AccessSETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes
The p53-inducible antiproliferative gene BTG2 is suppressed in many cancers, in the absence of inactivating gene mutations. Here the authors show that the histone lysine methyltransferase SETD1A suppresses the expression of several p53 target genes including BTG2by inducing a network of microRNAs.
- Ken Tajima
- , Toshifumi Yae
- & Shyamala Maheswaran
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Article
| Open AccessInternational genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways
Primary biliary cirrhosis is an autoimmune liver disease with poor therapeutic options. Here Cordell et al. a perform meta-analysis of European genome-wide association studies identifying six novel risk loci and a number of potential therapeutic pathways.
- Heather J. Cordell
- , Younghun Han
- & Katherine A. Siminovitch
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Article
| Open AccessImpaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia
Lukacs et al. identify mutations in the PIEZO1gene in patients with congenital lymphatic dysplasia. The study also characterizes the functional consequence of the disease-associated Piezo1 mutant proteins and show attenuated ion channel function in cellular context.
- Viktor Lukacs
- , Jayanti Mathur
- & Bryan L. Krock
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Article
| Open AccessIncreased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure
Transcription factor COUP-TFII is elevated in the hearts of non-ischaemic cardiomyopathy patients, but the nature of this correlation is unknown. Here the authors show that forced cardiac expression of COUP-TFII in mice causes dilated cardiomyopathy because of altered mitochondrial function and impaired metabolic remodelling.
- San-Pin Wu
- , Chung-Yang Kao
- & Sophia Y. Tsai
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Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis
Smad signalling has been implicated in tumour and metastases formation. Here, Tang et al.show that profilin-2 enhances Smad signalling and tumour growth via an epigenetic mechanism, and that Smad expression correlates with an unfavourable prognosis of lung cancer patients.
- Yun-Neng Tang
- , Wei-Qiao Ding
- & Jian-Guo Song
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Article
| Open AccessNovel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis
Primary lymphoedema can lead to the swelling of the extremities and facial dysmorphism. Here the authors present evidence that compound heterozygous and homozygous mutations inPIEZO1result in an autosomal recessive form of generalised lymphatic dysplasia.
- Elisavet Fotiou
- , Silvia Martin-Almedina
- & Pia Ostergaard
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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