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| 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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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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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
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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
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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
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| 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
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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
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| 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
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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
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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
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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
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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
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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
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| 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
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| 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
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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
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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
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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
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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
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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
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Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling
Matriptase, a transmembrane serine protease, has been implicated in breast cancer since its discovery, but the mechanisms of this implication have not been elucidated. Here the authors show that matriptase abrogation in vivoaffects c-Met signalling and the growth of breast cancer cells.
- Gina L. Zoratti
- , Lauren M. Tanabe
- & Karin List
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Skp2–MacroH2A1–CDK8 axis orchestrates G2/M transition and tumorigenesis
Skp2 forms part of the SCF complex—an E3 ubiquitin ligase. Here the authors identify macroH2A1 as a novel target of Skp2 and propose an axis of regulation involving Skp2-macroH2A1-CDK8-p27 in cancer.
- Dazhi Xu
- , Chien-Feng Li
- & Hui-Kuan Lin
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Article
| Open AccessRB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer
Resistance to tyrosine kinase inhibitors occurs in treatments of non-small-cell lung cancers (NSCLCs) with EGFR mutations but the mechanisms underlying this acquired resistance are unknown. Here the authors examine the molecular changes that occur in resistant cancers that transition from NSCLC to small-cell lung cancer phenotype and implicate loss of retinoblastoma in this process.
- Matthew J. Niederst
- , Lecia V. Sequist
- & Jeffrey A. Engelman
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The reverse evolution from multicellularity to unicellularity during carcinogenesis
Multicellularity relies on molecular mechanisms that promote cooperation of individual cells and limit their inappropriate expansion. Here Chen et al. show that genes unique to multicellular organisms are preferentially inactivated during tumour evolution.
- Han Chen
- , Fangqin Lin
- & Xionglei He
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Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia
Acinar-to-ductal metaplasia (ADM) is a potential early step in the development of pancreatic cancer. Here, using an in vitromodel of ADM, the authors show that protein kinase D1 (PKD1) is required for TGFα- or KRAS-induced ADM through Notch activation.
- Geou-Yarh Liou
- , Heike Döppler
- & Peter Storz
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Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis
The Hippo pathway is a major regulator of organ size and growth control. Here Wu et al. provide evidence for a novel link between the Hippo signalling pathway and the unfolded protein response (UPR) in regulating organ growth and tumorigenesis.
- Hongtan Wu
- , Luyao Wei
- & Dawang Zhou
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Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis
Activation of the liver receptor CAR and β-catenin are both involved in hepatocellular carcinoma. Here, the authors show that combined activation of both CAR and β-catenin in mice can drive uncontrolled liver growth and is sufficient for hepatocarcinogenesis.
- Bingning Dong
- , Ju-Seog Lee
- & David D. Moore
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| Open AccessAn oncogenic role of Agrin in regulating focal adhesion integrity in hepatocellular carcinoma
The proteoglycan Agrin is known to be expressed in neurons and muscle and to bind ECM protein laminin. Here the authors report that Agrin promotes hepatocellular carcinoma by stimulating proliferation, decreasing focal adhesion, increasing invasiveness and promoting an epithelial-to-mesenchymal transition.
- Sayan Chakraborty
- , Manikandan Lakshmanan
- & Wanjin Hong
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Coexistent ARID1A–PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling
ARID1A is frequently mutated in ovarian clear-cell carcinoma. Here the authors show that ARID1A loss in mice cooperates with PI3K activation to recapitulate the human disease, and implicate IL-6 signalling as the underlying mechanism.
- Ronald L. Chandler
- , Jeffrey S. Damrauer
- & Terry Magnuson
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| Open AccessInterfering with stem cell-specific gatekeeper functions controls tumour initiation and malignant progression of skin tumours
The presence of multiple stem and progenitor cells in the skin has a major impact on the formation of different epidermal tumours. Here the authors identify bulge stem cells as the cells of origin of sebaceous tumours through genetic lineage tracing and molecular studies in a mouse model.
- Monika Petersson
- , Karen Reuter
- & Catherin Niemann
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| Open AccessOncogenic Kit signals on endolysosomes and endoplasmic reticulum are essential for neoplastic mast cell proliferation
Activating mutations of the tyrosine kinase Kit are commonly found in mast cell neoplasms and gastrointestinal stromal tumours. Here the authors show that mutant Kit, through the activation of PI3K and STAT3 pathways, elicits proliferative and survival signals from endolysosomes and from the endoplasmic reticulum.
- Yuuki Obata
- , Shota Toyoshima
- & Ryo Abe
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Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner
The anti-apoptotic protein Mcl-1 and haplo-insufficient tumour suppressor Beclin-1 are deregulated in several cancers. Here the authors show that Mcl-1 and Beclin-1 compete for binding to the deubiquitinase USP9X, resulting in a reciprocal regulation during melanoma progression.
- Mohamed Elgendy
- , Marco Ciro
- & Saverio Minucci
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Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis
The transcription factor ZEB1 has been implicated in different steps of the metastatic cascade. Here the authors show that heterozygous loss of ZEB1in a K-Ras-driven mouse model of lung cancer inhibits progression from lung adenomas to adenocarcinomas.
- Yongqing Liu
- , Xiaoqin Lu
- & Douglas C. Dean
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PKM2 phosphorylates MLC2 and regulates cytokinesis of tumour cells
The pyruvate kinase type M2 (PKM2) has a well-established role in cancer due to its functions in regulating glucose metabolism, G1-S transition and mitotic checkpoint. Here the authors identified a novel role for PKM2 in regulating cytokinesis in cancer cells through the phosphorylation of the myosin light chain 2 at the contractile ring.
- Yuhui Jiang
- , Yugang Wang
- & Zhimin Lu
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Decreased tumorigenesis in mice with a Kras point mutation at C118
The Ras family of proteins is frequently mutated in cancer, and free radical oxidants can also activate these proteins via modifications at cysteine 118 (C118). Here the authors introduce a C118S mutant Krasgene into mice and show that this mutant allele results in a reduction in lung tumorigenesis.
- Lu Huang
- , John Carney
- & Christopher M. Counter
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CSN6 drives carcinogenesis by positively regulating Myc stability
The COP9 signalosome (CSN) is a protein complex involved in protein degradation and tumorigenesis. Here the authors show that the CSN6 subunit antagonizes the deneddylation function of CSN5 towards ubiquitin ligase Cullin-1, resulting in Fbxw7 ubiquitin ligase degradation and thereby stabilization of the Fbxw7 target Myc.
- Jian Chen
- , Ji-Hyun Shin
- & Mong-Hong Lee
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Article
| Open AccessChlamydia infection depends on a functional MDM2-p53 axis
Protein p53 plays key roles in cellular stress responses and is frequently deregulated in cancer. Here the authors show that infection with chlamydiae activates the ubiquitin ligase MDM2 in infected cells, leading to proteasomal degradation of p53 and thus promoting apoptosis resistance.
- Erik González
- , Marion Rother
- & Thomas F. Meyer
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| Open AccessNF-κB-induced KIAA1199 promotes survival through EGFR signalling
The cross-talk between constitutively active EGFR- and NF-κB-dependent pathways in cancer is poorly understood. Here, the authors identify KIAA1199 as a BCL3 and NF-κB-regulated protein that is expressed in cervical lesions and promotes tumorigenesis through Plexin A2 binding and regulation of EGFR stability.
- Kateryna Shostak
- , Xin Zhang
- & Alain Chariot
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| Open AccessGenomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis
Loss-of-function mutations in tumour suppressor genes are associated with oesophageal adenocarcinoma (EAC), but the mechanisms underlying EAC development remain unclear. Here, the authors show that EACs present a high frequency of genomic catastrophes resulting in amplification of potent oncogenes.
- Katia Nones
- , Nicola Waddell
- & Andrew P. Barbour
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Inflammation-driven carcinogenesis is mediated through STING
Chronic inflammation is known to promote tumorigenesis, but the mechanisms underlying this are incompletely understood. Here, the authors show that several carcinogens induce DNA leakage into the cytoplasm, which activates STING-dependent cytokine production and inflammation-driven tumorigenesis.
- Jeonghyun Ahn
- , Tianli Xia
- & Glen N. Barber
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Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis
Focal adhesion kinase (FAK) is frequently overexpressed in solid tumours. Here Batista et al.show that loss of FAK skews hematopoietic progenitors toward myeloid differentiation and promotes metastases, warning against the use of FAK inhibitors in anticancer therapies.
- Silvia Batista
- , Eleni Maniati
- & Kairbaan Hodivala-Dilke
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Spatial control of Cdc42 signalling by a GM130–RasGRF complex regulates polarity and tumorigenesis
The small GTPase Cdc42 is an important regulator of cell polarity that localizes to both the plasma membrane and to the Golgi. Baschieri et al.show that the Golgi pool of Cdc42 is regulated by GM130–RasGRF, and that deregulation of this pathway is associated with loss of polarity and tumorigenesis.
- Francesco Baschieri
- , Stefano Confalonieri
- & Hesso Farhan
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Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions
Several recent studies suggest that telomerase has key physiologic functions beyond its well-known role telomere maintenance. Here, Garcia Gonzalez et al. implicate telomerase in the regulation of ribosomal DNA transcription by RNA polymerase I.
- Omar Garcia Gonzalez
- , Robin Assfalg
- & Sebastian Iben
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BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells
Alternative splicing often alters the biological function of proteins. Here, Zhou et al. show that the splicing factor SRSF10 directs the inclusion of exon5a in Bcl-2-associated transcription factor 1, and that this drives cell growth and tumorigenic potential in human colon cancer cells.
- Xuexia Zhou
- , Xuebing Li
- & Ying Feng
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SOX2 is a cancer-specific regulator of tumour initiating potential in cutaneous squamous cell carcinoma
The mechanisms that sustain the self-renewal and expansion of cancer cells with tumour initiating potential are not completely understood. Here the authors show that the transcription factor, Sox2, marks tumour initiating cells in cutaneous squamous cell carcinomas and is required for their expansion.
- Jasmin M. Siegle
- , Alice Basin
- & Markus Schober
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| Open AccessHomeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing
Cells exposed to DNA damage delay mitotic entry to allow repair. Liang et al. unexpectedly find that the duration of arrest and the completeness of repair vary from cell to cell, determined by progressively increasing polo-like kinase-1 activity, which must pass a threshold to trigger mitosis.
- Hongqing Liang
- , Alessandro Esposito
- & Ashok R. Venkitaraman
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Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease
Ras family members have critical roles in many types of tumours but the role of R-Ras2 in cancer is unclear. Here the authors show that R-Ras2 is important in both the formation of breast primary tumours and metastasis to the lung.
- Romain M. Larive
- , Giulia Moriggi
- & Xosé R. Bustelo
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The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis
E3 ligases that attach ubiquitin to proteins destined for proteasomal degradation are regulated by neddylation. In this study, Xie et al. show that the HECT ligase Smurf1, which is a ubiquitin ligase, is also neddylated, and this post-translational modification enhances its ligase activity.
- Ping Xie
- , Minghua Zhang
- & Lingqiang Zhang
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Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4
The Ras oncogene has many different roles in cancer including the production of cytokines that can influence the tumour microenvironment. Here, Catanzaro et al.demonstrate that Ras can modulate the expression of SerpinB3/B4, which leads to increased cytokine production and tumour growth.
- Joseph M. Catanzaro
- , Namratha Sheshadri
- & Wei-Xing Zong