Repression of microRNA-768-3p by MEK/ERK signalling contributes to enhanced mRNA translation in human melanoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-06-17

AUTHORS

C C Jiang, A Croft, H-Y Tseng, S T Guo, L Jin, P Hersey, X D Zhang

ABSTRACT

Increased global protein synthesis and selective translation of mRNAs encoding proteins contributing to malignancy is common in cancer cells. This is often associated with elevated expression of eukaryotic translation initiation factor 4 (eIF4E), the rate-limiting factor of cap-dependent translation initiation. We report here that in human melanoma downregulation of miR-768-3p as a result of activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway has an important role in the upregulation of eIF4E and enhancement in protein synthesis. Melanoma cells displayed increased nascent protein production and elevated eIF4E expression, which was associated with the downregulation of miR-768-3p that was predicted to target the 3′-untranslated region of the eIF4E mRNA. Overexpression of miR-768-3p led to the downregulation of the endogenous eIF4E protein, reduction in nascent protein synthesis and inhibition of cell survival and proliferation. These effects were efficiently reversed when eIF4E was co-overexpressed in melanoma cells. On the other hand, introduction of anti-miR-768-3p into melanocytes upregulated endogenous eIF4E protein expression and increased global protein synthesis. Downregulation of miR-768-3p appeared to be mediated by activation of the MEK/ERK pathway, in that treatment of BRAFV600E melanoma cells with the mutant BRAF inhibitor PLX4720 or exposure of either BRAFV600E or wild-type BRAF melanoma cells to the MEK inhibitor U0126 resulted in the upregulation of miR-768-3p and inhibition of nascent protein synthesis. This inhibition was partially blocked in cells cointroduced with anti-miR-768-3p. Significantly, miR-768-3p was similarly downregulated, which was inversely associated with the expression levels of eIF4E in fresh melanoma isolates. Taken together, these results identify downregulation of miR-768-3p and subsequent upregulation of eIF4E as an important mechanism in addition to phosphorylation of eIF4E responsible for MEK/ERK-mediated enhancement of protein synthesis in melanoma. More... »

PAGES

2577-2588

References to SciGraph publications

  • 2010-04. Translational control in cancer in NATURE REVIEWS CANCER
  • 2010-02. The mechanism of eukaryotic translation initiation and principles of its regulation in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2011-03-21. Ets-1 mediates upregulation of Mcl-1 downstream of XBP-1 in human melanoma cells upon ER stress in ONCOGENE
  • 2010-07-02. Many ways to generate microRNA-like small RNAs: non-canonical pathways for microRNA production in MOLECULAR GENETICS AND GENOMICS
  • 2004-04-19. eIF-4E expression and its role in malignancies and metastases in ONCOGENE
  • 2007-04-02. Mechanisms of translational deregulation in human tumors and therapeutic intervention strategies in ONCOGENE
  • 2009-10. Causes and consequences of microRNA dysregulation in cancer in NATURE REVIEWS GENETICS
  • 2004-07. MicroRNAs: small RNAs with a big role in gene regulation in NATURE REVIEWS GENETICS
  • 2007-09-10. MNK1 and EIF4E are downstream effectors of MEKs in the regulation of the nuclear export of HDM2 mRNA in ONCOGENE
  • 2009-04-14. Combined analysis of eIF4E and 4E-binding protein expression predicts breast cancer survival and estimates eIF4E activity in BRITISH JOURNAL OF CANCER
  • 2012-07-02. Oncogenic B-Raf signaling in melanoma cells controls a network of microRNAs with combinatorial functions in ONCOGENE
  • 2004-04-19. The role of translation in neoplastic transformation from a pathologist's point of view in ONCOGENE
  • 2012-02-15. The microcosmos of cancer in NATURE
  • 2002-06-09. Mutations of the BRAF gene in human cancer in NATURE
  • 1990-06. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap in NATURE
  • 2012-06-18. MicroRNA-497 targets insulin-like growth factor 1 receptor and has a tumour suppressive role in human colorectal cancer in ONCOGENE
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/onc.2013.237

    DOI

    http://dx.doi.org/10.1038/onc.2013.237

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1020840119

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/23770856


    Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
    Incoming Citations Browse incoming citations for this publication using opencitations.net

    JSON-LD is the canonical representation for SciGraph data.

    TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

    [
      {
        "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
        "about": [
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/11", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Medical and Health Sciences", 
            "type": "DefinedTerm"
          }, 
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1103", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Clinical Sciences", 
            "type": "DefinedTerm"
          }, 
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1112", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Oncology and Carcinogenesis", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cell Line, Tumor", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Down-Regulation", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Eukaryotic Initiation Factor-4E", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Humans", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "MAP Kinase Signaling System", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Melanoma", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "MicroRNAs", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Protein Biosynthesis", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "RNA, Messenger", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Signal Transduction", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Up-Regulation", 
            "type": "DefinedTerm"
          }
        ], 
        "author": [
          {
            "affiliation": {
              "alternateName": "School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia", 
              "id": "http://www.grid.ac/institutes/grid.266842.c", 
              "name": [
                "Priority Research Centre for Cancer Research, University of Newcastle, Callaghan, NSW, Australia", 
                "School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Jiang", 
            "givenName": "C C", 
            "id": "sg:person.0617201523.26", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0617201523.26"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Oncology and Immunology Unit, Calvary Mater Newcastle Hospital, Waratah, NSW, Australia", 
              "id": "http://www.grid.ac/institutes/grid.413265.7", 
              "name": [
                "Priority Research Centre for Cancer Research, University of Newcastle, Callaghan, NSW, Australia", 
                "Oncology and Immunology Unit, Calvary Mater Newcastle Hospital, Waratah, NSW, Australia"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Croft", 
            "givenName": "A", 
            "id": "sg:person.01215144734.56", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01215144734.56"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia", 
              "id": "http://www.grid.ac/institutes/grid.266842.c", 
              "name": [
                "Priority Research Centre for Cancer Research, University of Newcastle, Callaghan, NSW, Australia", 
                "School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Tseng", 
            "givenName": "H-Y", 
            "id": "sg:person.01032164214.33", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01032164214.33"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, People\u2019s Republic of China", 
              "id": "http://www.grid.ac/institutes/None", 
              "name": [
                "Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, People\u2019s Republic of China"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Guo", 
            "givenName": "S T", 
            "id": "sg:person.01330754414.20", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01330754414.20"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Kolling Institute for Medical Research, University of Sydney, St Leonards, NSW, Australia", 
              "id": "http://www.grid.ac/institutes/grid.1013.3", 
              "name": [
                "Kolling Institute for Medical Research, University of Sydney, St Leonards, NSW, Australia"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Jin", 
            "givenName": "L", 
            "id": "sg:person.01246527316.15", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01246527316.15"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Kolling Institute for Medical Research, University of Sydney, St Leonards, NSW, Australia", 
              "id": "http://www.grid.ac/institutes/grid.1013.3", 
              "name": [
                "Kolling Institute for Medical Research, University of Sydney, St Leonards, NSW, Australia"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Hersey", 
            "givenName": "P", 
            "id": "sg:person.01073667716.42", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01073667716.42"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, People\u2019s Republic of China", 
              "id": "http://www.grid.ac/institutes/None", 
              "name": [
                "Priority Research Centre for Cancer Research, University of Newcastle, Callaghan, NSW, Australia", 
                "School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia", 
                "Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, People\u2019s Republic of China"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Zhang", 
            "givenName": "X D", 
            "id": "sg:person.01210116316.18", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01210116316.18"
            ], 
            "type": "Person"
          }
        ], 
        "citation": [
          {
            "id": "sg:pub.10.1038/sj.onc.1207552", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1024750458", 
              "https://doi.org/10.1038/sj.onc.1207552"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrg1379", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1001799892", 
              "https://doi.org/10.1038/nrg1379"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/sj.bjc.6605044", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1013480093", 
              "https://doi.org/10.1038/sj.bjc.6605044"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/345544a0", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1028554116", 
              "https://doi.org/10.1038/345544a0"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s00438-010-0556-1", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1040020818", 
              "https://doi.org/10.1007/s00438-010-0556-1"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrc2824", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1027786679", 
              "https://doi.org/10.1038/nrc2824"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/onc.2012.214", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1030059862", 
              "https://doi.org/10.1038/onc.2012.214"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nature00766", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1023536940", 
              "https://doi.org/10.1038/nature00766"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrg2634", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1040605557", 
              "https://doi.org/10.1038/nrg2634"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/sj.onc.1207545", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1041824710", 
              "https://doi.org/10.1038/sj.onc.1207545"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nature10888", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1020992751", 
              "https://doi.org/10.1038/nature10888"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/sj.onc.1210785", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1020132052", 
              "https://doi.org/10.1038/sj.onc.1210785"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/sj.onc.1210431", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1031069180", 
              "https://doi.org/10.1038/sj.onc.1210431"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrm2838", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1036173966", 
              "https://doi.org/10.1038/nrm2838"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/onc.2011.87", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1039031247", 
              "https://doi.org/10.1038/onc.2011.87"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/onc.2012.209", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1012426753", 
              "https://doi.org/10.1038/onc.2012.209"
            ], 
            "type": "CreativeWork"
          }
        ], 
        "datePublished": "2013-06-17", 
        "datePublishedReg": "2013-06-17", 
        "description": "Increased global protein synthesis and selective translation of mRNAs encoding proteins contributing to malignancy is common in cancer cells. This is often associated with elevated expression of eukaryotic translation initiation factor 4 (eIF4E), the rate-limiting factor of cap-dependent translation initiation. We report here that in human melanoma downregulation of miR-768-3p as a result of activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway has an important role in the upregulation of eIF4E and enhancement in protein synthesis. Melanoma cells displayed increased nascent protein production and elevated eIF4E expression, which was associated with the downregulation of miR-768-3p that was predicted to target the 3\u2032-untranslated region of the eIF4E mRNA. Overexpression of miR-768-3p led to the downregulation of the endogenous eIF4E protein, reduction in nascent protein synthesis and inhibition of cell survival and proliferation. These effects were efficiently reversed when eIF4E was co-overexpressed in melanoma cells. On the other hand, introduction of anti-miR-768-3p into melanocytes upregulated endogenous eIF4E protein expression and increased global protein synthesis. Downregulation of miR-768-3p appeared to be mediated by activation of the MEK/ERK pathway, in that treatment of BRAFV600E melanoma cells with the mutant BRAF inhibitor PLX4720 or exposure of either BRAFV600E or wild-type BRAF melanoma cells to the MEK inhibitor U0126 resulted in the upregulation of miR-768-3p and inhibition of nascent protein synthesis. This inhibition was partially blocked in cells cointroduced with anti-miR-768-3p. Significantly, miR-768-3p was similarly downregulated, which was inversely associated with the expression levels of eIF4E in fresh melanoma isolates. Taken together, these results identify downregulation of miR-768-3p and subsequent upregulation of eIF4E as an important mechanism in addition to phosphorylation of eIF4E responsible for MEK/ERK-mediated enhancement of protein synthesis in melanoma.", 
        "genre": "article", 
        "id": "sg:pub.10.1038/onc.2013.237", 
        "isAccessibleForFree": true, 
        "isPartOf": [
          {
            "id": "sg:journal.1097543", 
            "issn": [
              "0950-9232", 
              "1476-5594"
            ], 
            "name": "Oncogene", 
            "publisher": "Springer Nature", 
            "type": "Periodical"
          }, 
          {
            "issueNumber": "20", 
            "type": "PublicationIssue"
          }, 
          {
            "type": "PublicationVolume", 
            "volumeNumber": "33"
          }
        ], 
        "keywords": [
          "global protein synthesis", 
          "nascent protein synthesis", 
          "protein synthesis", 
          "cap-dependent translation initiation", 
          "eukaryotic translation initiation factor 4", 
          "signal-regulated kinase pathway", 
          "wild-type BRAF melanoma cells", 
          "melanoma cells", 
          "phosphorylation of eIF4E", 
          "protein kinase kinase", 
          "MEK/ERK pathway", 
          "MEK inhibitor U0126", 
          "MEK/ERK", 
          "fresh melanoma isolates", 
          "kinase kinase", 
          "translation initiation", 
          "eIF4E protein", 
          "selective translation", 
          "BRAF inhibitor PLX4720", 
          "mRNA translation", 
          "kinase pathway", 
          "eIF4E mRNA", 
          "eIF4E", 
          "protein production", 
          "ERK pathway", 
          "inhibitor U0126", 
          "cell survival", 
          "BRAFV600E melanoma cells", 
          "inhibitor PLX4720", 
          "rate-limiting factor", 
          "expression levels", 
          "elevated expression", 
          "protein expression", 
          "cancer cells", 
          "downregulation", 
          "subsequent upregulation", 
          "factor 4", 
          "human melanoma", 
          "protein", 
          "important mechanism", 
          "expression", 
          "cells", 
          "result of activation", 
          "upregulation", 
          "mRNA", 
          "Upregulation of eIF4E", 
          "pathway", 
          "important role", 
          "inhibition", 
          "activation", 
          "repression", 
          "kinase", 
          "phosphorylation", 
          "U0126", 
          "ERK", 
          "translation", 
          "overexpression", 
          "mitogen", 
          "PLX4720", 
          "proliferation", 
          "isolates", 
          "synthesis", 
          "BRAFV600E", 
          "contributes", 
          "mechanism", 
          "role", 
          "production", 
          "initiation", 
          "survival", 
          "melanoma", 
          "region", 
          "levels", 
          "factors", 
          "addition", 
          "exposure", 
          "results", 
          "effect", 
          "malignancy", 
          "enhancement", 
          "introduction", 
          "reduction", 
          "treatment", 
          "hand"
        ], 
        "name": "Repression of microRNA-768-3p by MEK/ERK signalling contributes to enhanced mRNA translation in human melanoma", 
        "pagination": "2577-2588", 
        "productId": [
          {
            "name": "dimensions_id", 
            "type": "PropertyValue", 
            "value": [
              "pub.1020840119"
            ]
          }, 
          {
            "name": "doi", 
            "type": "PropertyValue", 
            "value": [
              "10.1038/onc.2013.237"
            ]
          }, 
          {
            "name": "pubmed_id", 
            "type": "PropertyValue", 
            "value": [
              "23770856"
            ]
          }
        ], 
        "sameAs": [
          "https://doi.org/10.1038/onc.2013.237", 
          "https://app.dimensions.ai/details/publication/pub.1020840119"
        ], 
        "sdDataset": "articles", 
        "sdDatePublished": "2022-10-01T06:39", 
        "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
        "sdPublisher": {
          "name": "Springer Nature - SN SciGraph project", 
          "type": "Organization"
        }, 
        "sdSource": "s3://com-springernature-scigraph/baseset/20221001/entities/gbq_results/article/article_604.jsonl", 
        "type": "ScholarlyArticle", 
        "url": "https://doi.org/10.1038/onc.2013.237"
      }
    ]
     

    Download the RDF metadata as:  json-ld nt turtle xml License info

    HOW TO GET THIS DATA PROGRAMMATICALLY:

    JSON-LD is a popular format for linked data which is fully compatible with JSON.

    curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/onc.2013.237'

    N-Triples is a line-based linked data format ideal for batch operations.

    curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/onc.2013.237'

    Turtle is a human-readable linked data format.

    curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/onc.2013.237'

    RDF/XML is a standard XML format for linked data.

    curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/onc.2013.237'


     

    This table displays all metadata directly associated to this object as RDF triples.

    311 TRIPLES      21 PREDICATES      136 URIs      111 LITERALS      18 BLANK NODES

    Subject Predicate Object
    1 sg:pub.10.1038/onc.2013.237 schema:about N0c5a238f163f4e5a8739a8dad50fdbbf
    2 N33815f1848f748ff99b58ac8e13aa20d
    3 N46b4571379974192accbc564affb16b2
    4 N61ff9b1afec94422a73576d34ec25fc0
    5 N6f507e01e6d54536bd267e2914671e06
    6 N8bfb12b4d903404da861d216d67b05ed
    7 Nd44835e6287548ab8a7c7d010f904cc4
    8 Ne50e950b223c48e18cd6bae900d59628
    9 Ne5bfb75d641f432aad3cd05271df62b3
    10 Needca21dfa4a48b986c842b5f91d383e
    11 Nf0f139bb4b894c35b702cd8b2597cbb2
    12 anzsrc-for:11
    13 anzsrc-for:1103
    14 anzsrc-for:1112
    15 schema:author Nf8e17aa94111406c9a8363506fcc4e99
    16 schema:citation sg:pub.10.1007/s00438-010-0556-1
    17 sg:pub.10.1038/345544a0
    18 sg:pub.10.1038/nature00766
    19 sg:pub.10.1038/nature10888
    20 sg:pub.10.1038/nrc2824
    21 sg:pub.10.1038/nrg1379
    22 sg:pub.10.1038/nrg2634
    23 sg:pub.10.1038/nrm2838
    24 sg:pub.10.1038/onc.2011.87
    25 sg:pub.10.1038/onc.2012.209
    26 sg:pub.10.1038/onc.2012.214
    27 sg:pub.10.1038/sj.bjc.6605044
    28 sg:pub.10.1038/sj.onc.1207545
    29 sg:pub.10.1038/sj.onc.1207552
    30 sg:pub.10.1038/sj.onc.1210431
    31 sg:pub.10.1038/sj.onc.1210785
    32 schema:datePublished 2013-06-17
    33 schema:datePublishedReg 2013-06-17
    34 schema:description Increased global protein synthesis and selective translation of mRNAs encoding proteins contributing to malignancy is common in cancer cells. This is often associated with elevated expression of eukaryotic translation initiation factor 4 (eIF4E), the rate-limiting factor of cap-dependent translation initiation. We report here that in human melanoma downregulation of miR-768-3p as a result of activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway has an important role in the upregulation of eIF4E and enhancement in protein synthesis. Melanoma cells displayed increased nascent protein production and elevated eIF4E expression, which was associated with the downregulation of miR-768-3p that was predicted to target the 3′-untranslated region of the eIF4E mRNA. Overexpression of miR-768-3p led to the downregulation of the endogenous eIF4E protein, reduction in nascent protein synthesis and inhibition of cell survival and proliferation. These effects were efficiently reversed when eIF4E was co-overexpressed in melanoma cells. On the other hand, introduction of anti-miR-768-3p into melanocytes upregulated endogenous eIF4E protein expression and increased global protein synthesis. Downregulation of miR-768-3p appeared to be mediated by activation of the MEK/ERK pathway, in that treatment of BRAFV600E melanoma cells with the mutant BRAF inhibitor PLX4720 or exposure of either BRAFV600E or wild-type BRAF melanoma cells to the MEK inhibitor U0126 resulted in the upregulation of miR-768-3p and inhibition of nascent protein synthesis. This inhibition was partially blocked in cells cointroduced with anti-miR-768-3p. Significantly, miR-768-3p was similarly downregulated, which was inversely associated with the expression levels of eIF4E in fresh melanoma isolates. Taken together, these results identify downregulation of miR-768-3p and subsequent upregulation of eIF4E as an important mechanism in addition to phosphorylation of eIF4E responsible for MEK/ERK-mediated enhancement of protein synthesis in melanoma.
    35 schema:genre article
    36 schema:isAccessibleForFree true
    37 schema:isPartOf N34243ced9aa2411fa2a9fe679dc07b28
    38 N7a16b75ee50041098741ef204ab02ead
    39 sg:journal.1097543
    40 schema:keywords BRAF inhibitor PLX4720
    41 BRAFV600E
    42 BRAFV600E melanoma cells
    43 ERK
    44 ERK pathway
    45 MEK inhibitor U0126
    46 MEK/ERK
    47 MEK/ERK pathway
    48 PLX4720
    49 U0126
    50 Upregulation of eIF4E
    51 activation
    52 addition
    53 cancer cells
    54 cap-dependent translation initiation
    55 cell survival
    56 cells
    57 contributes
    58 downregulation
    59 eIF4E
    60 eIF4E mRNA
    61 eIF4E protein
    62 effect
    63 elevated expression
    64 enhancement
    65 eukaryotic translation initiation factor 4
    66 exposure
    67 expression
    68 expression levels
    69 factor 4
    70 factors
    71 fresh melanoma isolates
    72 global protein synthesis
    73 hand
    74 human melanoma
    75 important mechanism
    76 important role
    77 inhibition
    78 inhibitor PLX4720
    79 inhibitor U0126
    80 initiation
    81 introduction
    82 isolates
    83 kinase
    84 kinase kinase
    85 kinase pathway
    86 levels
    87 mRNA
    88 mRNA translation
    89 malignancy
    90 mechanism
    91 melanoma
    92 melanoma cells
    93 mitogen
    94 nascent protein synthesis
    95 overexpression
    96 pathway
    97 phosphorylation
    98 phosphorylation of eIF4E
    99 production
    100 proliferation
    101 protein
    102 protein expression
    103 protein kinase kinase
    104 protein production
    105 protein synthesis
    106 rate-limiting factor
    107 reduction
    108 region
    109 repression
    110 result of activation
    111 results
    112 role
    113 selective translation
    114 signal-regulated kinase pathway
    115 subsequent upregulation
    116 survival
    117 synthesis
    118 translation
    119 translation initiation
    120 treatment
    121 upregulation
    122 wild-type BRAF melanoma cells
    123 schema:name Repression of microRNA-768-3p by MEK/ERK signalling contributes to enhanced mRNA translation in human melanoma
    124 schema:pagination 2577-2588
    125 schema:productId N3ed431b519c14aa1a160b840795df776
    126 Ncdce3ecfccd44ea497ab50259283cfd6
    127 Ne2669e5a918f4a89990e0cf3f7aa0b40
    128 schema:sameAs https://app.dimensions.ai/details/publication/pub.1020840119
    129 https://doi.org/10.1038/onc.2013.237
    130 schema:sdDatePublished 2022-10-01T06:39
    131 schema:sdLicense https://scigraph.springernature.com/explorer/license/
    132 schema:sdPublisher N7c6eea426de744c3a2f7423c33e469b0
    133 schema:url https://doi.org/10.1038/onc.2013.237
    134 sgo:license sg:explorer/license/
    135 sgo:sdDataset articles
    136 rdf:type schema:ScholarlyArticle
    137 N0c5a238f163f4e5a8739a8dad50fdbbf schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    138 schema:name Eukaryotic Initiation Factor-4E
    139 rdf:type schema:DefinedTerm
    140 N33815f1848f748ff99b58ac8e13aa20d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    141 schema:name MicroRNAs
    142 rdf:type schema:DefinedTerm
    143 N34243ced9aa2411fa2a9fe679dc07b28 schema:volumeNumber 33
    144 rdf:type schema:PublicationVolume
    145 N39040629e3094527935bd3eb6b3b3ff3 rdf:first sg:person.01210116316.18
    146 rdf:rest rdf:nil
    147 N3ed431b519c14aa1a160b840795df776 schema:name dimensions_id
    148 schema:value pub.1020840119
    149 rdf:type schema:PropertyValue
    150 N46b4571379974192accbc564affb16b2 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    151 schema:name Humans
    152 rdf:type schema:DefinedTerm
    153 N61ff9b1afec94422a73576d34ec25fc0 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    154 schema:name RNA, Messenger
    155 rdf:type schema:DefinedTerm
    156 N6f507e01e6d54536bd267e2914671e06 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    157 schema:name Up-Regulation
    158 rdf:type schema:DefinedTerm
    159 N74ab87c5f7964126a77921447953a837 rdf:first sg:person.01032164214.33
    160 rdf:rest Nfc6c8cceddf74b55834f1d5ff1690e68
    161 N7a16b75ee50041098741ef204ab02ead schema:issueNumber 20
    162 rdf:type schema:PublicationIssue
    163 N7c6eea426de744c3a2f7423c33e469b0 schema:name Springer Nature - SN SciGraph project
    164 rdf:type schema:Organization
    165 N82e949020ef14702b05603722c29749d rdf:first sg:person.01073667716.42
    166 rdf:rest N39040629e3094527935bd3eb6b3b3ff3
    167 N88192c32fd784b54996f7fea5eea343e rdf:first sg:person.01215144734.56
    168 rdf:rest N74ab87c5f7964126a77921447953a837
    169 N8bfb12b4d903404da861d216d67b05ed schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    170 schema:name Signal Transduction
    171 rdf:type schema:DefinedTerm
    172 Ncdce3ecfccd44ea497ab50259283cfd6 schema:name doi
    173 schema:value 10.1038/onc.2013.237
    174 rdf:type schema:PropertyValue
    175 Nd44835e6287548ab8a7c7d010f904cc4 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    176 schema:name Protein Biosynthesis
    177 rdf:type schema:DefinedTerm
    178 Ne2669e5a918f4a89990e0cf3f7aa0b40 schema:name pubmed_id
    179 schema:value 23770856
    180 rdf:type schema:PropertyValue
    181 Ne50e950b223c48e18cd6bae900d59628 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    182 schema:name Down-Regulation
    183 rdf:type schema:DefinedTerm
    184 Ne5bfb75d641f432aad3cd05271df62b3 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    185 schema:name Melanoma
    186 rdf:type schema:DefinedTerm
    187 Needca21dfa4a48b986c842b5f91d383e schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    188 schema:name MAP Kinase Signaling System
    189 rdf:type schema:DefinedTerm
    190 Nf0f139bb4b894c35b702cd8b2597cbb2 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    191 schema:name Cell Line, Tumor
    192 rdf:type schema:DefinedTerm
    193 Nf4dcba3e61024000b6292c781e48bb23 rdf:first sg:person.01246527316.15
    194 rdf:rest N82e949020ef14702b05603722c29749d
    195 Nf8e17aa94111406c9a8363506fcc4e99 rdf:first sg:person.0617201523.26
    196 rdf:rest N88192c32fd784b54996f7fea5eea343e
    197 Nfc6c8cceddf74b55834f1d5ff1690e68 rdf:first sg:person.01330754414.20
    198 rdf:rest Nf4dcba3e61024000b6292c781e48bb23
    199 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
    200 schema:name Medical and Health Sciences
    201 rdf:type schema:DefinedTerm
    202 anzsrc-for:1103 schema:inDefinedTermSet anzsrc-for:
    203 schema:name Clinical Sciences
    204 rdf:type schema:DefinedTerm
    205 anzsrc-for:1112 schema:inDefinedTermSet anzsrc-for:
    206 schema:name Oncology and Carcinogenesis
    207 rdf:type schema:DefinedTerm
    208 sg:journal.1097543 schema:issn 0950-9232
    209 1476-5594
    210 schema:name Oncogene
    211 schema:publisher Springer Nature
    212 rdf:type schema:Periodical
    213 sg:person.01032164214.33 schema:affiliation grid-institutes:grid.266842.c
    214 schema:familyName Tseng
    215 schema:givenName H-Y
    216 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01032164214.33
    217 rdf:type schema:Person
    218 sg:person.01073667716.42 schema:affiliation grid-institutes:grid.1013.3
    219 schema:familyName Hersey
    220 schema:givenName P
    221 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01073667716.42
    222 rdf:type schema:Person
    223 sg:person.01210116316.18 schema:affiliation grid-institutes:None
    224 schema:familyName Zhang
    225 schema:givenName X D
    226 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01210116316.18
    227 rdf:type schema:Person
    228 sg:person.01215144734.56 schema:affiliation grid-institutes:grid.413265.7
    229 schema:familyName Croft
    230 schema:givenName A
    231 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01215144734.56
    232 rdf:type schema:Person
    233 sg:person.01246527316.15 schema:affiliation grid-institutes:grid.1013.3
    234 schema:familyName Jin
    235 schema:givenName L
    236 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01246527316.15
    237 rdf:type schema:Person
    238 sg:person.01330754414.20 schema:affiliation grid-institutes:None
    239 schema:familyName Guo
    240 schema:givenName S T
    241 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01330754414.20
    242 rdf:type schema:Person
    243 sg:person.0617201523.26 schema:affiliation grid-institutes:grid.266842.c
    244 schema:familyName Jiang
    245 schema:givenName C C
    246 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0617201523.26
    247 rdf:type schema:Person
    248 sg:pub.10.1007/s00438-010-0556-1 schema:sameAs https://app.dimensions.ai/details/publication/pub.1040020818
    249 https://doi.org/10.1007/s00438-010-0556-1
    250 rdf:type schema:CreativeWork
    251 sg:pub.10.1038/345544a0 schema:sameAs https://app.dimensions.ai/details/publication/pub.1028554116
    252 https://doi.org/10.1038/345544a0
    253 rdf:type schema:CreativeWork
    254 sg:pub.10.1038/nature00766 schema:sameAs https://app.dimensions.ai/details/publication/pub.1023536940
    255 https://doi.org/10.1038/nature00766
    256 rdf:type schema:CreativeWork
    257 sg:pub.10.1038/nature10888 schema:sameAs https://app.dimensions.ai/details/publication/pub.1020992751
    258 https://doi.org/10.1038/nature10888
    259 rdf:type schema:CreativeWork
    260 sg:pub.10.1038/nrc2824 schema:sameAs https://app.dimensions.ai/details/publication/pub.1027786679
    261 https://doi.org/10.1038/nrc2824
    262 rdf:type schema:CreativeWork
    263 sg:pub.10.1038/nrg1379 schema:sameAs https://app.dimensions.ai/details/publication/pub.1001799892
    264 https://doi.org/10.1038/nrg1379
    265 rdf:type schema:CreativeWork
    266 sg:pub.10.1038/nrg2634 schema:sameAs https://app.dimensions.ai/details/publication/pub.1040605557
    267 https://doi.org/10.1038/nrg2634
    268 rdf:type schema:CreativeWork
    269 sg:pub.10.1038/nrm2838 schema:sameAs https://app.dimensions.ai/details/publication/pub.1036173966
    270 https://doi.org/10.1038/nrm2838
    271 rdf:type schema:CreativeWork
    272 sg:pub.10.1038/onc.2011.87 schema:sameAs https://app.dimensions.ai/details/publication/pub.1039031247
    273 https://doi.org/10.1038/onc.2011.87
    274 rdf:type schema:CreativeWork
    275 sg:pub.10.1038/onc.2012.209 schema:sameAs https://app.dimensions.ai/details/publication/pub.1012426753
    276 https://doi.org/10.1038/onc.2012.209
    277 rdf:type schema:CreativeWork
    278 sg:pub.10.1038/onc.2012.214 schema:sameAs https://app.dimensions.ai/details/publication/pub.1030059862
    279 https://doi.org/10.1038/onc.2012.214
    280 rdf:type schema:CreativeWork
    281 sg:pub.10.1038/sj.bjc.6605044 schema:sameAs https://app.dimensions.ai/details/publication/pub.1013480093
    282 https://doi.org/10.1038/sj.bjc.6605044
    283 rdf:type schema:CreativeWork
    284 sg:pub.10.1038/sj.onc.1207545 schema:sameAs https://app.dimensions.ai/details/publication/pub.1041824710
    285 https://doi.org/10.1038/sj.onc.1207545
    286 rdf:type schema:CreativeWork
    287 sg:pub.10.1038/sj.onc.1207552 schema:sameAs https://app.dimensions.ai/details/publication/pub.1024750458
    288 https://doi.org/10.1038/sj.onc.1207552
    289 rdf:type schema:CreativeWork
    290 sg:pub.10.1038/sj.onc.1210431 schema:sameAs https://app.dimensions.ai/details/publication/pub.1031069180
    291 https://doi.org/10.1038/sj.onc.1210431
    292 rdf:type schema:CreativeWork
    293 sg:pub.10.1038/sj.onc.1210785 schema:sameAs https://app.dimensions.ai/details/publication/pub.1020132052
    294 https://doi.org/10.1038/sj.onc.1210785
    295 rdf:type schema:CreativeWork
    296 grid-institutes:None schema:alternateName Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, People’s Republic of China
    297 schema:name Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, People’s Republic of China
    298 Priority Research Centre for Cancer Research, University of Newcastle, Callaghan, NSW, Australia
    299 School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia
    300 rdf:type schema:Organization
    301 grid-institutes:grid.1013.3 schema:alternateName Kolling Institute for Medical Research, University of Sydney, St Leonards, NSW, Australia
    302 schema:name Kolling Institute for Medical Research, University of Sydney, St Leonards, NSW, Australia
    303 rdf:type schema:Organization
    304 grid-institutes:grid.266842.c schema:alternateName School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia
    305 schema:name Priority Research Centre for Cancer Research, University of Newcastle, Callaghan, NSW, Australia
    306 School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia
    307 rdf:type schema:Organization
    308 grid-institutes:grid.413265.7 schema:alternateName Oncology and Immunology Unit, Calvary Mater Newcastle Hospital, Waratah, NSW, Australia
    309 schema:name Oncology and Immunology Unit, Calvary Mater Newcastle Hospital, Waratah, NSW, Australia
    310 Priority Research Centre for Cancer Research, University of Newcastle, Callaghan, NSW, Australia
    311 rdf:type schema:Organization
     




    Preview window. Press ESC to close (or click here)


    ...