CRL4AMBRA1 is a master regulator of D-type cyclins View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2021-04-14

AUTHORS

Daniele Simoneschi, Gergely Rona, Nan Zhou, Yeon-Tae Jeong, Shaowen Jiang, Giacomo Milletti, Arnaldo A. Arbini, Alfie O’Sullivan, Andrew A. Wang, Sorasicha Nithikasem, Sarah Keegan, Yik Siu, Valentina Cianfanelli, Emiliano Maiani, Francesca Nazio, Francesco Cecconi, Francesco Boccalatte, David Fenyö, Drew R. Jones, Luca Busino, Michele Pagano

ABSTRACT

D-type cyclins are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer1, but the mechanisms that regulate their turnover are still being debated2,3. Here, by combining biochemical and genetics studies in somatic cells, we identify CRL4AMBRA1 (also known as CRL4DCAF3) as the ubiquitin ligase that targets all three D-type cyclins for degradation. During development, loss of Ambra1 induces the accumulation of D-type cyclins and retinoblastoma (RB) hyperphosphorylation and hyperproliferation, and results in defects of the nervous system that are reduced by treating pregnant mice with the FDA-approved CDK4 and CDK6 (CDK4/6) inhibitor abemaciclib. Moreover, AMBRA1 acts as a tumour suppressor in mouse models and low AMBRA1 mRNA levels are predictive of poor survival in cancer patients. Cancer hotspot mutations in D-type cyclins abrogate their binding to AMBRA1 and induce their stabilization. Finally, a whole-genome, CRISPR–Cas9 screen identified AMBRA1 as a regulator of the response to CDK4/6 inhibition. Loss of AMBRA1 reduces sensitivity to CDK4/6 inhibitors by promoting the formation of complexes of D-type cyclins with CDK2. Collectively, our results reveal the molecular mechanism that controls the stability of D-type cyclins during cell-cycle progression, in development and in human cancer, and implicate AMBRA1 as a critical regulator of the RB pathway. More... »

PAGES

789-793

References to SciGraph publications

  • 2017-03-20. The TDH–GCN5L1–Fbxo15–KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells in NATURE CELL BIOLOGY
  • 2010-07-27. ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67 in BREAST CANCER RESEARCH
  • 1997-05. Regulation of p53 stability by Mdm2 in NATURE
  • 2009-03. Cell cycle, CDKs and cancer: a changing paradigm in NATURE REVIEWS CANCER
  • 2017-06-14. PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth in NATURE
  • 1999-05. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis in NATURE
  • 2013-10-24. Genome engineering using the CRISPR-Cas9 system in NATURE PROTOCOLS
  • 2014-07-30. Improved vectors and genome-wide libraries for CRISPR screening in NATURE METHODS
  • 2016-03-23. Fair Statistical Communication in HCI in MODERN STATISTICAL METHODS FOR HCI
  • 2015-01-30. The history and future of targeting cyclin-dependent kinases in cancer therapy in NATURE REVIEWS DRUG DISCOVERY
  • 2009-09-21. Lysine 269 is essential for cyclin D1 ubiquitylation by the SCFFbx4/αB-crystallin ligase and subsequent proteasome-dependent degradation in ONCOGENE
  • 2014-04-06. De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in NATURE GENETICS
  • 2009-05-03. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma in NATURE
  • 2019-04-10. Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens in NATURE
  • 2007-06-24. Ambra1 regulates autophagy and development of the nervous system in NATURE
  • 2014-12-05. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens in GENOME BIOLOGY
  • 2020-09-22. VAV2 signaling promotes regenerative proliferation in both cutaneous and head and neck squamous cell carcinoma in NATURE COMMUNICATIONS
  • 2012-08-12. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics in NATURE
  • 2018-12-10. The molecular landscape of glioma in patients with Neurofibromatosis 1 in NATURE MEDICINE
  • 2009-05-03. F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage in NATURE
  • 2019-12-05. The SMART App: an interactive web application for comprehensive DNA methylation analysis and visualization in EPIGENETICS & CHROMATIN
  • Journal

    TITLE

    Nature

    ISSUE

    7856

    VOLUME

    592

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41586-021-03445-y

    DOI

    http://dx.doi.org/10.1038/s41586-021-03445-y

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1137190996

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/33854235


    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/2008/06", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Biological Sciences", 
            "type": "DefinedTerm"
          }, 
          {
            "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/2008/0601", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Biochemistry and Cell Biology", 
            "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": "Adaptor Proteins, Signal Transducing", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Animals", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "CRISPR-Cas Systems", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cell Division", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cyclin D1", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cyclin D2", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cyclin D3", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cyclin-Dependent Kinase 2", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cyclin-Dependent Kinase 4", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cyclin-Dependent Kinase 6", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Female", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Gene Knockout Techniques", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Genes, Tumor Suppressor", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "HCT116 Cells", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "HEK293 Cells", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Humans", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Male", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Mice", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Neoplasms", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Ubiquitin", 
            "type": "DefinedTerm"
          }
        ], 
        "author": [
          {
            "affiliation": {
              "alternateName": "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.240324.3", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Simoneschi", 
            "givenName": "Daniele", 
            "id": "sg:person.015553121003.83", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.015553121003.83"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.137628.9", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
                "Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Rona", 
            "givenName": "Gergely", 
            "id": "sg:person.01344541536.04", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01344541536.04"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA", 
              "id": "http://www.grid.ac/institutes/grid.25879.31", 
              "name": [
                "Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Zhou", 
            "givenName": "Nan", 
            "id": "sg:person.012574050324.10", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.012574050324.10"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.240324.3", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Jeong", 
            "givenName": "Yeon-Tae", 
            "id": "sg:person.01272407271.15", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01272407271.15"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.240324.3", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Jiang", 
            "givenName": "Shaowen", 
            "id": "sg:person.010622413153.78", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010622413153.78"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Department of Biology, University of Rome Tor Vergata, Rome, Italy", 
              "id": "http://www.grid.ac/institutes/grid.6530.0", 
              "name": [
                "Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS Bambino Ges\u00f9 Children\u2019s Hospital, Rome, Italy", 
                "Department of Biology, University of Rome Tor Vergata, Rome, Italy"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Milletti", 
            "givenName": "Giacomo", 
            "id": "sg:person.011250122531.73", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.011250122531.73"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.137628.9", 
              "name": [
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
                "Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Arbini", 
            "givenName": "Arnaldo A.", 
            "id": "sg:person.0601520217.06", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0601520217.06"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.240324.3", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "O\u2019Sullivan", 
            "givenName": "Alfie", 
            "id": "sg:person.015505604077.33", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.015505604077.33"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.240324.3", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Wang", 
            "givenName": "Andrew A.", 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.240324.3", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Nithikasem", 
            "givenName": "Sorasicha", 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.137628.9", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
                "Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Keegan", 
            "givenName": "Sarah", 
            "id": "sg:person.01201372755.94", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01201372755.94"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.137628.9", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Siu", 
            "givenName": "Yik", 
            "id": "sg:person.01026251016.15", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01026251016.15"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark", 
              "id": "http://www.grid.ac/institutes/grid.417390.8", 
              "name": [
                "Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS Bambino Ges\u00f9 Children\u2019s Hospital, Rome, Italy", 
                "Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Cianfanelli", 
            "givenName": "Valentina", 
            "id": "sg:person.01235675046.11", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01235675046.11"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark", 
              "id": "http://www.grid.ac/institutes/grid.417390.8", 
              "name": [
                "Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark", 
                "Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Maiani", 
            "givenName": "Emiliano", 
            "id": "sg:person.01206214251.05", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01206214251.05"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS Bambino Ges\u00f9 Children\u2019s Hospital, Rome, Italy", 
              "id": "http://www.grid.ac/institutes/grid.414125.7", 
              "name": [
                "Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS Bambino Ges\u00f9 Children\u2019s Hospital, Rome, Italy"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Nazio", 
            "givenName": "Francesca", 
            "id": "sg:person.0745417347.56", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0745417347.56"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark", 
              "id": "http://www.grid.ac/institutes/grid.417390.8", 
              "name": [
                "Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS Bambino Ges\u00f9 Children\u2019s Hospital, Rome, Italy", 
                "Department of Biology, University of Rome Tor Vergata, Rome, Italy", 
                "Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Cecconi", 
            "givenName": "Francesco", 
            "id": "sg:person.01244666067.03", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01244666067.03"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.137628.9", 
              "name": [
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
                "Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Boccalatte", 
            "givenName": "Francesco", 
            "id": "sg:person.01335412574.23", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01335412574.23"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.137628.9", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
                "Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Feny\u00f6", 
            "givenName": "David", 
            "id": "sg:person.01237226535.22", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01237226535.22"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.137628.9", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Jones", 
            "givenName": "Drew R.", 
            "id": "sg:person.01150400617.24", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01150400617.24"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA", 
              "id": "http://www.grid.ac/institutes/grid.25879.31", 
              "name": [
                "Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Busino", 
            "givenName": "Luca", 
            "id": "sg:person.01172012050.68", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01172012050.68"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.137628.9", 
              "name": [
                "Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA", 
                "Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA", 
                "Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Pagano", 
            "givenName": "Michele", 
            "id": "sg:person.014643072472.18", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.014643072472.18"
            ], 
            "type": "Person"
          }
        ], 
        "citation": [
          {
            "id": "sg:pub.10.1186/s13072-019-0316-3", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1123151206", 
              "https://doi.org/10.1186/s13072-019-0316-3"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/s41586-019-1103-9", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1113356021", 
              "https://doi.org/10.1038/s41586-019-1103-9"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/20459", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1020261903", 
              "https://doi.org/10.1038/20459"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/s41591-018-0263-8", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1110405323", 
              "https://doi.org/10.1038/s41591-018-0263-8"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/ng.2948", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1006459416", 
              "https://doi.org/10.1038/ng.2948"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nature08011", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1035009231", 
              "https://doi.org/10.1038/nature08011"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/onc.2009.287", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1030242128", 
              "https://doi.org/10.1038/onc.2009.287"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrc2602", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1008867916", 
              "https://doi.org/10.1038/nrc2602"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1186/bcr2615", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1040240632", 
              "https://doi.org/10.1186/bcr2615"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nprot.2013.143", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1016534425", 
              "https://doi.org/10.1038/nprot.2013.143"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nature07968", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1047607151", 
              "https://doi.org/10.1038/nature07968"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nmeth.3047", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1003995336", 
              "https://doi.org/10.1038/nmeth.3047"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nature11378", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1007597995", 
              "https://doi.org/10.1038/nature11378"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nature22965", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1086021685", 
              "https://doi.org/10.1038/nature22965"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/s41467-020-18524-3", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1131074968", 
              "https://doi.org/10.1038/s41467-020-18524-3"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrd4504", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1021914398", 
              "https://doi.org/10.1038/nrd4504"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/387299a0", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1037935695", 
              "https://doi.org/10.1038/387299a0"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/ncb3491", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1084128691", 
              "https://doi.org/10.1038/ncb3491"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/978-3-319-26633-6_13", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1019586382", 
              "https://doi.org/10.1007/978-3-319-26633-6_13"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1186/s13059-014-0554-4", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1014314357", 
              "https://doi.org/10.1186/s13059-014-0554-4"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nature05925", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1007246070", 
              "https://doi.org/10.1038/nature05925"
            ], 
            "type": "CreativeWork"
          }
        ], 
        "datePublished": "2021-04-14", 
        "datePublishedReg": "2021-04-14", 
        "description": "D-type cyclins are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer1, but the mechanisms that regulate their turnover are still being debated2,3. Here, by\u00a0combining biochemical and genetics studies in somatic cells, we identify CRL4AMBRA1 (also known as CRL4DCAF3) as the ubiquitin ligase that targets all three D-type cyclins for degradation. During development, loss of Ambra1 induces the\u00a0accumulation of D-type cyclins and\u00a0retinoblastoma (RB) hyperphosphorylation and hyperproliferation, and results in defects of the nervous system\u00a0that are reduced by treating pregnant mice with the FDA-approved CDK4 and CDK6 (CDK4/6) inhibitor abemaciclib. Moreover, AMBRA1 acts as a tumour suppressor in mouse models and low AMBRA1 mRNA levels are predictive of poor survival in cancer patients. Cancer hotspot mutations in D-type cyclins abrogate their binding to AMBRA1 and induce their stabilization. Finally, a whole-genome, CRISPR\u2013Cas9 screen identified AMBRA1 as a regulator of the response to CDK4/6 inhibition. Loss of AMBRA1 reduces sensitivity to CDK4/6 inhibitors by promoting the formation of complexes of D-type cyclins with CDK2. Collectively, our results reveal the molecular mechanism that controls the stability of D-type cyclins during cell-cycle progression, in development and in human cancer, and implicate AMBRA1 as a critical regulator of the RB pathway.", 
        "genre": "article", 
        "id": "sg:pub.10.1038/s41586-021-03445-y", 
        "isAccessibleForFree": true, 
        "isFundedItemOf": [
          {
            "id": "sg:grant.5503934", 
            "type": "MonetaryGrant"
          }, 
          {
            "id": "sg:grant.9063693", 
            "type": "MonetaryGrant"
          }, 
          {
            "id": "sg:grant.2473483", 
            "type": "MonetaryGrant"
          }, 
          {
            "id": "sg:grant.2438822", 
            "type": "MonetaryGrant"
          }, 
          {
            "id": "sg:grant.9011829", 
            "type": "MonetaryGrant"
          }, 
          {
            "id": "sg:grant.3492540", 
            "type": "MonetaryGrant"
          }, 
          {
            "id": "sg:grant.9012646", 
            "type": "MonetaryGrant"
          }
        ], 
        "isPartOf": [
          {
            "id": "sg:journal.1018957", 
            "issn": [
              "0028-0836", 
              "1476-4687"
            ], 
            "name": "Nature", 
            "publisher": "Springer Nature", 
            "type": "Periodical"
          }, 
          {
            "issueNumber": "7856", 
            "type": "PublicationIssue"
          }, 
          {
            "type": "PublicationVolume", 
            "volumeNumber": "592"
          }
        ], 
        "keywords": [
          "D-type cyclins", 
          "loss of AMBRA1", 
          "cell division cycle", 
          "cell cycle progression", 
          "division cycle", 
          "ubiquitin ligase", 
          "somatic cells", 
          "master regulator", 
          "central regulator", 
          "retinoblastoma hyperphosphorylation", 
          "AMBRA1", 
          "tumor suppressor", 
          "molecular mechanisms", 
          "critical regulator", 
          "genetic studies", 
          "Rb pathway", 
          "cancer hotspot mutations", 
          "cyclin", 
          "human cancers", 
          "human cancer1", 
          "regulator", 
          "mRNA levels", 
          "therapeutic target", 
          "hotspot mutations", 
          "formation of complexes", 
          "cancer patients", 
          "CDK4/6 inhibition", 
          "CDK4/6 inhibitors", 
          "pregnant mice", 
          "poor survival", 
          "mouse model", 
          "nervous system", 
          "ligase", 
          "CRISPR", 
          "suppressor", 
          "CDK2", 
          "hyperphosphorylation", 
          "mutations", 
          "pathway", 
          "CDK4", 
          "mechanism", 
          "binding", 
          "biochemical", 
          "turnover", 
          "cells", 
          "accumulation", 
          "hyperproliferation", 
          "inhibitors", 
          "complexes", 
          "screen", 
          "inhibition", 
          "target", 
          "patients", 
          "abemaciclib", 
          "degradation", 
          "cancer", 
          "loss", 
          "development", 
          "mice", 
          "Cancer1", 
          "progression", 
          "survival", 
          "FDA", 
          "cycle", 
          "defects", 
          "response", 
          "formation", 
          "levels", 
          "stabilization", 
          "study", 
          "results", 
          "sensitivity", 
          "stability", 
          "system", 
          "model"
        ], 
        "name": "CRL4AMBRA1 is a master regulator of D-type cyclins", 
        "pagination": "789-793", 
        "productId": [
          {
            "name": "dimensions_id", 
            "type": "PropertyValue", 
            "value": [
              "pub.1137190996"
            ]
          }, 
          {
            "name": "doi", 
            "type": "PropertyValue", 
            "value": [
              "10.1038/s41586-021-03445-y"
            ]
          }, 
          {
            "name": "pubmed_id", 
            "type": "PropertyValue", 
            "value": [
              "33854235"
            ]
          }
        ], 
        "sameAs": [
          "https://doi.org/10.1038/s41586-021-03445-y", 
          "https://app.dimensions.ai/details/publication/pub.1137190996"
        ], 
        "sdDataset": "articles", 
        "sdDatePublished": "2022-08-04T17:10", 
        "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
        "sdPublisher": {
          "name": "Springer Nature - SN SciGraph project", 
          "type": "Organization"
        }, 
        "sdSource": "s3://com-springernature-scigraph/baseset/20220804/entities/gbq_results/article/article_884.jsonl", 
        "type": "ScholarlyArticle", 
        "url": "https://doi.org/10.1038/s41586-021-03445-y"
      }
    ]
     

    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/s41586-021-03445-y'

    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/s41586-021-03445-y'

    Turtle is a human-readable linked data format.

    curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/s41586-021-03445-y'

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

    curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/s41586-021-03445-y'


     

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

    488 TRIPLES      21 PREDICATES      143 URIs      112 LITERALS      27 BLANK NODES

    Subject Predicate Object
    1 sg:pub.10.1038/s41586-021-03445-y schema:about N04f1d16c2ac04ad485338b2bf4d3a8cd
    2 N05e32ca11a6b4acc80fc72f22be624ef
    3 N227a7b154cb14722a06bd430e32cb4d8
    4 N2d856af375e04f4bb6b2e3b2e82c45ad
    5 N31ab038ef3fa4ad7b8a63329d1b1c807
    6 N379f231a097d4483b00934fbfa1fd915
    7 N60eddd7c9f734a2bace26d3235578db7
    8 N7ca1af39f5d44ac48d390e2bdc70da41
    9 N9c7d44d81db84756a07a5fb03c48ff5f
    10 N9ce746b2fbaf4229a3cb82682ecbc19b
    11 Na25aab4c5c9d41a3b4f70b097a37a2ce
    12 Nb7d937767eaf4ec9a7666afb7465f59f
    13 Nb8002453921148cb8bbf513449e70e59
    14 Nbad64690b953481c9a460c708897059a
    15 Nbb70e343dbbf4afe8ddc319c420d526f
    16 Nc51abb763a69401399062fa6a5f5d968
    17 Ncb3bdd078c984e3fb916cf0792805ea0
    18 Ndb0edaafedbd4459818da8caa7c1e81e
    19 Nddb91c61f6a743f2b2bbdc25162266ec
    20 Nfe6d10ad90db4065a4993b24b323348d
    21 anzsrc-for:06
    22 anzsrc-for:0601
    23 anzsrc-for:11
    24 anzsrc-for:1112
    25 schema:author Ne01eb222a24f43b4ae82e5c9d6a22e71
    26 schema:citation sg:pub.10.1007/978-3-319-26633-6_13
    27 sg:pub.10.1038/20459
    28 sg:pub.10.1038/387299a0
    29 sg:pub.10.1038/nature05925
    30 sg:pub.10.1038/nature07968
    31 sg:pub.10.1038/nature08011
    32 sg:pub.10.1038/nature11378
    33 sg:pub.10.1038/nature22965
    34 sg:pub.10.1038/ncb3491
    35 sg:pub.10.1038/ng.2948
    36 sg:pub.10.1038/nmeth.3047
    37 sg:pub.10.1038/nprot.2013.143
    38 sg:pub.10.1038/nrc2602
    39 sg:pub.10.1038/nrd4504
    40 sg:pub.10.1038/onc.2009.287
    41 sg:pub.10.1038/s41467-020-18524-3
    42 sg:pub.10.1038/s41586-019-1103-9
    43 sg:pub.10.1038/s41591-018-0263-8
    44 sg:pub.10.1186/bcr2615
    45 sg:pub.10.1186/s13059-014-0554-4
    46 sg:pub.10.1186/s13072-019-0316-3
    47 schema:datePublished 2021-04-14
    48 schema:datePublishedReg 2021-04-14
    49 schema:description D-type cyclins are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer1, but the mechanisms that regulate their turnover are still being debated2,3. Here, by combining biochemical and genetics studies in somatic cells, we identify CRL4AMBRA1 (also known as CRL4DCAF3) as the ubiquitin ligase that targets all three D-type cyclins for degradation. During development, loss of Ambra1 induces the accumulation of D-type cyclins and retinoblastoma (RB) hyperphosphorylation and hyperproliferation, and results in defects of the nervous system that are reduced by treating pregnant mice with the FDA-approved CDK4 and CDK6 (CDK4/6) inhibitor abemaciclib. Moreover, AMBRA1 acts as a tumour suppressor in mouse models and low AMBRA1 mRNA levels are predictive of poor survival in cancer patients. Cancer hotspot mutations in D-type cyclins abrogate their binding to AMBRA1 and induce their stabilization. Finally, a whole-genome, CRISPR–Cas9 screen identified AMBRA1 as a regulator of the response to CDK4/6 inhibition. Loss of AMBRA1 reduces sensitivity to CDK4/6 inhibitors by promoting the formation of complexes of D-type cyclins with CDK2. Collectively, our results reveal the molecular mechanism that controls the stability of D-type cyclins during cell-cycle progression, in development and in human cancer, and implicate AMBRA1 as a critical regulator of the RB pathway.
    50 schema:genre article
    51 schema:isAccessibleForFree true
    52 schema:isPartOf Na22b0d63cbbf4c768e41b77609a8ae00
    53 Nf7760e3f3f844138885807671773f81e
    54 sg:journal.1018957
    55 schema:keywords AMBRA1
    56 CDK2
    57 CDK4
    58 CDK4/6 inhibition
    59 CDK4/6 inhibitors
    60 CRISPR
    61 Cancer1
    62 D-type cyclins
    63 FDA
    64 Rb pathway
    65 abemaciclib
    66 accumulation
    67 binding
    68 biochemical
    69 cancer
    70 cancer hotspot mutations
    71 cancer patients
    72 cell cycle progression
    73 cell division cycle
    74 cells
    75 central regulator
    76 complexes
    77 critical regulator
    78 cycle
    79 cyclin
    80 defects
    81 degradation
    82 development
    83 division cycle
    84 formation
    85 formation of complexes
    86 genetic studies
    87 hotspot mutations
    88 human cancer1
    89 human cancers
    90 hyperphosphorylation
    91 hyperproliferation
    92 inhibition
    93 inhibitors
    94 levels
    95 ligase
    96 loss
    97 loss of AMBRA1
    98 mRNA levels
    99 master regulator
    100 mechanism
    101 mice
    102 model
    103 molecular mechanisms
    104 mouse model
    105 mutations
    106 nervous system
    107 pathway
    108 patients
    109 poor survival
    110 pregnant mice
    111 progression
    112 regulator
    113 response
    114 results
    115 retinoblastoma hyperphosphorylation
    116 screen
    117 sensitivity
    118 somatic cells
    119 stability
    120 stabilization
    121 study
    122 suppressor
    123 survival
    124 system
    125 target
    126 therapeutic target
    127 tumor suppressor
    128 turnover
    129 ubiquitin ligase
    130 schema:name CRL4AMBRA1 is a master regulator of D-type cyclins
    131 schema:pagination 789-793
    132 schema:productId N47a1ea13a46d4658848eec99758adbe9
    133 Na587e3f8d91e46ab93d88b6cace2e790
    134 Nc38ec7b1206e4017b0a3a5df85c6d79b
    135 schema:sameAs https://app.dimensions.ai/details/publication/pub.1137190996
    136 https://doi.org/10.1038/s41586-021-03445-y
    137 schema:sdDatePublished 2022-08-04T17:10
    138 schema:sdLicense https://scigraph.springernature.com/explorer/license/
    139 schema:sdPublisher Na667af0a97f94c1185299232f70e6f0f
    140 schema:url https://doi.org/10.1038/s41586-021-03445-y
    141 sgo:license sg:explorer/license/
    142 sgo:sdDataset articles
    143 rdf:type schema:ScholarlyArticle
    144 N04f1d16c2ac04ad485338b2bf4d3a8cd schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    145 schema:name Cyclin-Dependent Kinase 2
    146 rdf:type schema:DefinedTerm
    147 N05e32ca11a6b4acc80fc72f22be624ef schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    148 schema:name CRISPR-Cas Systems
    149 rdf:type schema:DefinedTerm
    150 N1bb0d018d2a34e6693a8bfeeff9e3d5e rdf:first sg:person.010622413153.78
    151 rdf:rest Nea07a8b73f9641dcb47c3ca7d81f52ed
    152 N227a7b154cb14722a06bd430e32cb4d8 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    153 schema:name Cyclin-Dependent Kinase 4
    154 rdf:type schema:DefinedTerm
    155 N2a6d852c0b1e42968952fd441acefecc rdf:first sg:person.01237226535.22
    156 rdf:rest Ne73e42d71f8a45968c43e1e7cfc6130d
    157 N2d856af375e04f4bb6b2e3b2e82c45ad schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    158 schema:name HCT116 Cells
    159 rdf:type schema:DefinedTerm
    160 N2e30915130d04e76a4b809d910f79fdd rdf:first sg:person.01344541536.04
    161 rdf:rest N80459f95685849d788bc196fd8a8f83f
    162 N31ab038ef3fa4ad7b8a63329d1b1c807 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    163 schema:name HEK293 Cells
    164 rdf:type schema:DefinedTerm
    165 N31e777b953dc44788a60c8d77d6f387e rdf:first sg:person.01172012050.68
    166 rdf:rest N4e1e869fc5fe46c0a9eb9b57d3fb8286
    167 N379f231a097d4483b00934fbfa1fd915 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    168 schema:name Cell Division
    169 rdf:type schema:DefinedTerm
    170 N47a1ea13a46d4658848eec99758adbe9 schema:name pubmed_id
    171 schema:value 33854235
    172 rdf:type schema:PropertyValue
    173 N4e1e869fc5fe46c0a9eb9b57d3fb8286 rdf:first sg:person.014643072472.18
    174 rdf:rest rdf:nil
    175 N60eddd7c9f734a2bace26d3235578db7 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    176 schema:name Mice
    177 rdf:type schema:DefinedTerm
    178 N67ff083f6cf340af8e8b81b9f0169e94 rdf:first sg:person.0745417347.56
    179 rdf:rest Nb51eeef93f6e465d8f61499215687d4a
    180 N732e622bc5fd48c38b537e1ca9e721fa schema:affiliation grid-institutes:grid.240324.3
    181 schema:familyName Wang
    182 schema:givenName Andrew A.
    183 rdf:type schema:Person
    184 N74082db8c3ca42a39391f5ad09019ca9 rdf:first N732e622bc5fd48c38b537e1ca9e721fa
    185 rdf:rest N778c98e74c074459bc5514a40b6b401d
    186 N778c98e74c074459bc5514a40b6b401d rdf:first Nb9549a6c24f04a57902354a0b8a272e0
    187 rdf:rest Nd646e3e38d7e415db49fd6a7d383548f
    188 N7ca1af39f5d44ac48d390e2bdc70da41 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    189 schema:name Female
    190 rdf:type schema:DefinedTerm
    191 N7d2814f4ec5d4c009450cd9fedbab4f1 rdf:first sg:person.01272407271.15
    192 rdf:rest N1bb0d018d2a34e6693a8bfeeff9e3d5e
    193 N80459f95685849d788bc196fd8a8f83f rdf:first sg:person.012574050324.10
    194 rdf:rest N7d2814f4ec5d4c009450cd9fedbab4f1
    195 N8a6d893477cf4cfda048fada9dbb36f5 rdf:first sg:person.0601520217.06
    196 rdf:rest Ncbe6d66317984c3eb2359404be5a1698
    197 N8bddbfbeeadd41eab6b147aa9a2f376f rdf:first sg:person.01235675046.11
    198 rdf:rest Nd3a1e503d0444b6ba94369171f27aa6f
    199 N9c7d44d81db84756a07a5fb03c48ff5f schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    200 schema:name Cyclin D1
    201 rdf:type schema:DefinedTerm
    202 N9ce746b2fbaf4229a3cb82682ecbc19b schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    203 schema:name Male
    204 rdf:type schema:DefinedTerm
    205 Na22b0d63cbbf4c768e41b77609a8ae00 schema:volumeNumber 592
    206 rdf:type schema:PublicationVolume
    207 Na25aab4c5c9d41a3b4f70b097a37a2ce schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    208 schema:name Ubiquitin
    209 rdf:type schema:DefinedTerm
    210 Na587e3f8d91e46ab93d88b6cace2e790 schema:name dimensions_id
    211 schema:value pub.1137190996
    212 rdf:type schema:PropertyValue
    213 Na667af0a97f94c1185299232f70e6f0f schema:name Springer Nature - SN SciGraph project
    214 rdf:type schema:Organization
    215 Nb51eeef93f6e465d8f61499215687d4a rdf:first sg:person.01244666067.03
    216 rdf:rest Nfd4a122c620a42a2a32c67ddd991d91e
    217 Nb7d937767eaf4ec9a7666afb7465f59f schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    218 schema:name Genes, Tumor Suppressor
    219 rdf:type schema:DefinedTerm
    220 Nb8002453921148cb8bbf513449e70e59 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    221 schema:name Cyclin-Dependent Kinase 6
    222 rdf:type schema:DefinedTerm
    223 Nb9549a6c24f04a57902354a0b8a272e0 schema:affiliation grid-institutes:grid.240324.3
    224 schema:familyName Nithikasem
    225 schema:givenName Sorasicha
    226 rdf:type schema:Person
    227 Nbad64690b953481c9a460c708897059a schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    228 schema:name Animals
    229 rdf:type schema:DefinedTerm
    230 Nbb70e343dbbf4afe8ddc319c420d526f schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    231 schema:name Humans
    232 rdf:type schema:DefinedTerm
    233 Nc38ec7b1206e4017b0a3a5df85c6d79b schema:name doi
    234 schema:value 10.1038/s41586-021-03445-y
    235 rdf:type schema:PropertyValue
    236 Nc51abb763a69401399062fa6a5f5d968 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    237 schema:name Neoplasms
    238 rdf:type schema:DefinedTerm
    239 Ncb3bdd078c984e3fb916cf0792805ea0 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    240 schema:name Adaptor Proteins, Signal Transducing
    241 rdf:type schema:DefinedTerm
    242 Ncbe6d66317984c3eb2359404be5a1698 rdf:first sg:person.015505604077.33
    243 rdf:rest N74082db8c3ca42a39391f5ad09019ca9
    244 Nd3a1e503d0444b6ba94369171f27aa6f rdf:first sg:person.01206214251.05
    245 rdf:rest N67ff083f6cf340af8e8b81b9f0169e94
    246 Nd646e3e38d7e415db49fd6a7d383548f rdf:first sg:person.01201372755.94
    247 rdf:rest Nedd846ce98be491face61df86a1d3833
    248 Ndb0edaafedbd4459818da8caa7c1e81e schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    249 schema:name Cyclin D3
    250 rdf:type schema:DefinedTerm
    251 Nddb91c61f6a743f2b2bbdc25162266ec schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    252 schema:name Gene Knockout Techniques
    253 rdf:type schema:DefinedTerm
    254 Ne01eb222a24f43b4ae82e5c9d6a22e71 rdf:first sg:person.015553121003.83
    255 rdf:rest N2e30915130d04e76a4b809d910f79fdd
    256 Ne73e42d71f8a45968c43e1e7cfc6130d rdf:first sg:person.01150400617.24
    257 rdf:rest N31e777b953dc44788a60c8d77d6f387e
    258 Nea07a8b73f9641dcb47c3ca7d81f52ed rdf:first sg:person.011250122531.73
    259 rdf:rest N8a6d893477cf4cfda048fada9dbb36f5
    260 Nedd846ce98be491face61df86a1d3833 rdf:first sg:person.01026251016.15
    261 rdf:rest N8bddbfbeeadd41eab6b147aa9a2f376f
    262 Nf7760e3f3f844138885807671773f81e schema:issueNumber 7856
    263 rdf:type schema:PublicationIssue
    264 Nfd4a122c620a42a2a32c67ddd991d91e rdf:first sg:person.01335412574.23
    265 rdf:rest N2a6d852c0b1e42968952fd441acefecc
    266 Nfe6d10ad90db4065a4993b24b323348d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    267 schema:name Cyclin D2
    268 rdf:type schema:DefinedTerm
    269 anzsrc-for:06 schema:inDefinedTermSet anzsrc-for:
    270 schema:name Biological Sciences
    271 rdf:type schema:DefinedTerm
    272 anzsrc-for:0601 schema:inDefinedTermSet anzsrc-for:
    273 schema:name Biochemistry and Cell Biology
    274 rdf:type schema:DefinedTerm
    275 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
    276 schema:name Medical and Health Sciences
    277 rdf:type schema:DefinedTerm
    278 anzsrc-for:1112 schema:inDefinedTermSet anzsrc-for:
    279 schema:name Oncology and Carcinogenesis
    280 rdf:type schema:DefinedTerm
    281 sg:grant.2438822 http://pending.schema.org/fundedItem sg:pub.10.1038/s41586-021-03445-y
    282 rdf:type schema:MonetaryGrant
    283 sg:grant.2473483 http://pending.schema.org/fundedItem sg:pub.10.1038/s41586-021-03445-y
    284 rdf:type schema:MonetaryGrant
    285 sg:grant.3492540 http://pending.schema.org/fundedItem sg:pub.10.1038/s41586-021-03445-y
    286 rdf:type schema:MonetaryGrant
    287 sg:grant.5503934 http://pending.schema.org/fundedItem sg:pub.10.1038/s41586-021-03445-y
    288 rdf:type schema:MonetaryGrant
    289 sg:grant.9011829 http://pending.schema.org/fundedItem sg:pub.10.1038/s41586-021-03445-y
    290 rdf:type schema:MonetaryGrant
    291 sg:grant.9012646 http://pending.schema.org/fundedItem sg:pub.10.1038/s41586-021-03445-y
    292 rdf:type schema:MonetaryGrant
    293 sg:grant.9063693 http://pending.schema.org/fundedItem sg:pub.10.1038/s41586-021-03445-y
    294 rdf:type schema:MonetaryGrant
    295 sg:journal.1018957 schema:issn 0028-0836
    296 1476-4687
    297 schema:name Nature
    298 schema:publisher Springer Nature
    299 rdf:type schema:Periodical
    300 sg:person.01026251016.15 schema:affiliation grid-institutes:grid.137628.9
    301 schema:familyName Siu
    302 schema:givenName Yik
    303 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01026251016.15
    304 rdf:type schema:Person
    305 sg:person.010622413153.78 schema:affiliation grid-institutes:grid.240324.3
    306 schema:familyName Jiang
    307 schema:givenName Shaowen
    308 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010622413153.78
    309 rdf:type schema:Person
    310 sg:person.011250122531.73 schema:affiliation grid-institutes:grid.6530.0
    311 schema:familyName Milletti
    312 schema:givenName Giacomo
    313 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.011250122531.73
    314 rdf:type schema:Person
    315 sg:person.01150400617.24 schema:affiliation grid-institutes:grid.137628.9
    316 schema:familyName Jones
    317 schema:givenName Drew R.
    318 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01150400617.24
    319 rdf:type schema:Person
    320 sg:person.01172012050.68 schema:affiliation grid-institutes:grid.25879.31
    321 schema:familyName Busino
    322 schema:givenName Luca
    323 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01172012050.68
    324 rdf:type schema:Person
    325 sg:person.01201372755.94 schema:affiliation grid-institutes:grid.137628.9
    326 schema:familyName Keegan
    327 schema:givenName Sarah
    328 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01201372755.94
    329 rdf:type schema:Person
    330 sg:person.01206214251.05 schema:affiliation grid-institutes:grid.417390.8
    331 schema:familyName Maiani
    332 schema:givenName Emiliano
    333 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01206214251.05
    334 rdf:type schema:Person
    335 sg:person.01235675046.11 schema:affiliation grid-institutes:grid.417390.8
    336 schema:familyName Cianfanelli
    337 schema:givenName Valentina
    338 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01235675046.11
    339 rdf:type schema:Person
    340 sg:person.01237226535.22 schema:affiliation grid-institutes:grid.137628.9
    341 schema:familyName Fenyö
    342 schema:givenName David
    343 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01237226535.22
    344 rdf:type schema:Person
    345 sg:person.01244666067.03 schema:affiliation grid-institutes:grid.417390.8
    346 schema:familyName Cecconi
    347 schema:givenName Francesco
    348 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01244666067.03
    349 rdf:type schema:Person
    350 sg:person.012574050324.10 schema:affiliation grid-institutes:grid.25879.31
    351 schema:familyName Zhou
    352 schema:givenName Nan
    353 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.012574050324.10
    354 rdf:type schema:Person
    355 sg:person.01272407271.15 schema:affiliation grid-institutes:grid.240324.3
    356 schema:familyName Jeong
    357 schema:givenName Yeon-Tae
    358 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01272407271.15
    359 rdf:type schema:Person
    360 sg:person.01335412574.23 schema:affiliation grid-institutes:grid.137628.9
    361 schema:familyName Boccalatte
    362 schema:givenName Francesco
    363 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01335412574.23
    364 rdf:type schema:Person
    365 sg:person.01344541536.04 schema:affiliation grid-institutes:grid.137628.9
    366 schema:familyName Rona
    367 schema:givenName Gergely
    368 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01344541536.04
    369 rdf:type schema:Person
    370 sg:person.014643072472.18 schema:affiliation grid-institutes:grid.137628.9
    371 schema:familyName Pagano
    372 schema:givenName Michele
    373 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.014643072472.18
    374 rdf:type schema:Person
    375 sg:person.015505604077.33 schema:affiliation grid-institutes:grid.240324.3
    376 schema:familyName O’Sullivan
    377 schema:givenName Alfie
    378 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.015505604077.33
    379 rdf:type schema:Person
    380 sg:person.015553121003.83 schema:affiliation grid-institutes:grid.240324.3
    381 schema:familyName Simoneschi
    382 schema:givenName Daniele
    383 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.015553121003.83
    384 rdf:type schema:Person
    385 sg:person.0601520217.06 schema:affiliation grid-institutes:grid.137628.9
    386 schema:familyName Arbini
    387 schema:givenName Arnaldo A.
    388 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0601520217.06
    389 rdf:type schema:Person
    390 sg:person.0745417347.56 schema:affiliation grid-institutes:grid.414125.7
    391 schema:familyName Nazio
    392 schema:givenName Francesca
    393 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0745417347.56
    394 rdf:type schema:Person
    395 sg:pub.10.1007/978-3-319-26633-6_13 schema:sameAs https://app.dimensions.ai/details/publication/pub.1019586382
    396 https://doi.org/10.1007/978-3-319-26633-6_13
    397 rdf:type schema:CreativeWork
    398 sg:pub.10.1038/20459 schema:sameAs https://app.dimensions.ai/details/publication/pub.1020261903
    399 https://doi.org/10.1038/20459
    400 rdf:type schema:CreativeWork
    401 sg:pub.10.1038/387299a0 schema:sameAs https://app.dimensions.ai/details/publication/pub.1037935695
    402 https://doi.org/10.1038/387299a0
    403 rdf:type schema:CreativeWork
    404 sg:pub.10.1038/nature05925 schema:sameAs https://app.dimensions.ai/details/publication/pub.1007246070
    405 https://doi.org/10.1038/nature05925
    406 rdf:type schema:CreativeWork
    407 sg:pub.10.1038/nature07968 schema:sameAs https://app.dimensions.ai/details/publication/pub.1047607151
    408 https://doi.org/10.1038/nature07968
    409 rdf:type schema:CreativeWork
    410 sg:pub.10.1038/nature08011 schema:sameAs https://app.dimensions.ai/details/publication/pub.1035009231
    411 https://doi.org/10.1038/nature08011
    412 rdf:type schema:CreativeWork
    413 sg:pub.10.1038/nature11378 schema:sameAs https://app.dimensions.ai/details/publication/pub.1007597995
    414 https://doi.org/10.1038/nature11378
    415 rdf:type schema:CreativeWork
    416 sg:pub.10.1038/nature22965 schema:sameAs https://app.dimensions.ai/details/publication/pub.1086021685
    417 https://doi.org/10.1038/nature22965
    418 rdf:type schema:CreativeWork
    419 sg:pub.10.1038/ncb3491 schema:sameAs https://app.dimensions.ai/details/publication/pub.1084128691
    420 https://doi.org/10.1038/ncb3491
    421 rdf:type schema:CreativeWork
    422 sg:pub.10.1038/ng.2948 schema:sameAs https://app.dimensions.ai/details/publication/pub.1006459416
    423 https://doi.org/10.1038/ng.2948
    424 rdf:type schema:CreativeWork
    425 sg:pub.10.1038/nmeth.3047 schema:sameAs https://app.dimensions.ai/details/publication/pub.1003995336
    426 https://doi.org/10.1038/nmeth.3047
    427 rdf:type schema:CreativeWork
    428 sg:pub.10.1038/nprot.2013.143 schema:sameAs https://app.dimensions.ai/details/publication/pub.1016534425
    429 https://doi.org/10.1038/nprot.2013.143
    430 rdf:type schema:CreativeWork
    431 sg:pub.10.1038/nrc2602 schema:sameAs https://app.dimensions.ai/details/publication/pub.1008867916
    432 https://doi.org/10.1038/nrc2602
    433 rdf:type schema:CreativeWork
    434 sg:pub.10.1038/nrd4504 schema:sameAs https://app.dimensions.ai/details/publication/pub.1021914398
    435 https://doi.org/10.1038/nrd4504
    436 rdf:type schema:CreativeWork
    437 sg:pub.10.1038/onc.2009.287 schema:sameAs https://app.dimensions.ai/details/publication/pub.1030242128
    438 https://doi.org/10.1038/onc.2009.287
    439 rdf:type schema:CreativeWork
    440 sg:pub.10.1038/s41467-020-18524-3 schema:sameAs https://app.dimensions.ai/details/publication/pub.1131074968
    441 https://doi.org/10.1038/s41467-020-18524-3
    442 rdf:type schema:CreativeWork
    443 sg:pub.10.1038/s41586-019-1103-9 schema:sameAs https://app.dimensions.ai/details/publication/pub.1113356021
    444 https://doi.org/10.1038/s41586-019-1103-9
    445 rdf:type schema:CreativeWork
    446 sg:pub.10.1038/s41591-018-0263-8 schema:sameAs https://app.dimensions.ai/details/publication/pub.1110405323
    447 https://doi.org/10.1038/s41591-018-0263-8
    448 rdf:type schema:CreativeWork
    449 sg:pub.10.1186/bcr2615 schema:sameAs https://app.dimensions.ai/details/publication/pub.1040240632
    450 https://doi.org/10.1186/bcr2615
    451 rdf:type schema:CreativeWork
    452 sg:pub.10.1186/s13059-014-0554-4 schema:sameAs https://app.dimensions.ai/details/publication/pub.1014314357
    453 https://doi.org/10.1186/s13059-014-0554-4
    454 rdf:type schema:CreativeWork
    455 sg:pub.10.1186/s13072-019-0316-3 schema:sameAs https://app.dimensions.ai/details/publication/pub.1123151206
    456 https://doi.org/10.1186/s13072-019-0316-3
    457 rdf:type schema:CreativeWork
    458 grid-institutes:grid.137628.9 schema:alternateName Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
    459 Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA
    460 Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, USA
    461 Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA
    462 schema:name Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
    463 Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA
    464 Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, USA
    465 Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA
    466 Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA
    467 rdf:type schema:Organization
    468 grid-institutes:grid.240324.3 schema:alternateName Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA
    469 schema:name Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
    470 Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA
    471 rdf:type schema:Organization
    472 grid-institutes:grid.25879.31 schema:alternateName Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
    473 schema:name Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
    474 rdf:type schema:Organization
    475 grid-institutes:grid.414125.7 schema:alternateName Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
    476 schema:name Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
    477 rdf:type schema:Organization
    478 grid-institutes:grid.417390.8 schema:alternateName Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark
    479 Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark
    480 schema:name Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark
    481 Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark
    482 Department of Biology, University of Rome Tor Vergata, Rome, Italy
    483 Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
    484 rdf:type schema:Organization
    485 grid-institutes:grid.6530.0 schema:alternateName Department of Biology, University of Rome Tor Vergata, Rome, Italy
    486 schema:name Department of Biology, University of Rome Tor Vergata, Rome, Italy
    487 Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
    488 rdf:type schema:Organization
     




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


    ...