DOI: 10.1073/pnas.0405495102. The p53 regulatory gene<i>MDM2</i>is a direct transcriptional target of MYCN in neuroblastoma

The p53 regulatory geneMDM2is a direct transcriptional target of MYCN in neuroblastoma

10.1073/pnas.0405495102

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

TheMYCNoncogene is the major negative prognostic marker in neuroblastoma with important roles in both the pathogenesis and clinical behavior of this aggressive malignancy.MYConcogenes activate both proliferative and apoptotic cellular pathways and, accordingly, inhibition of p53-mediated apoptosis is a prerequisite for MYC-driven tumorigenesis. To identify novel transcriptional targets mediating the MYCN-dependent phenotype, we screened a MYCN-amplified neuroblastoma cell line by using chromatin immunoprecipitation (ChIP) cloning. We identified the essential p53 inhibitor and protooncogeneMDM2as a putative target. MDM2 has multiple p53-independent functions modulating cell cycle and transcriptional events. Standard ChIP with MYCN antibodies established the binding of MYCN to a consensus E-box within the humanMDM2promoter. Oligonucleotide pull-down assays further established the capacity of MYCN to bind to this promoter region, confirming the ChIP results. Luciferase reporter assays confirmed the E-box-specific, MYCN-dependent regulation of theMDM2promoter in MYCN-inducible neuroblastoma cell lines. Real-time quantitative PCR and Western blot analysis demonstrated a rapid increase in endogenousMDM2mRNA and MDM2 protein upon induction of MYCN. Targeted inhibition of MYCN in aMYCN-amplified neuroblastoma cell line resulted in decreased MDM2 expression levels with concomitant stabilization of p53 and induction of apoptosis. Our finding that MYCN directly modulates baseline MDM2 levels suggests a mechanism contributing to the pathogenesis of neuroblastoma and other MYC-driven malignancies through inhibition of MYC-stimulated apoptosis.

Bibliography

Slack, A., Chen, Z., Tonelli, R., Pule, M., Hunt, L., Pession, A., & Shohet, J. M. (2005). The p53 regulatory geneMDM2is a direct transcriptional target of MYCN in neuroblastoma. Proceedings of the National Academy of Sciences, 102(3), 731â736.

Authors 7

Andrew Slack (first)
Zaowen Chen (additional)
Roberto Tonelli (additional)
Martin Pule (additional)
Lisa Hunt (additional)
Andrea Pession (additional)
Jason M. Shohet (additional)

References 48 Referenced 188

10.1056/NEJM199910143411601
10.1016/S0304-3835(03)00454-3
10.1093/emboj/16.11.2985
Schweigerer, L., Breit, S., Wenzel, A., Tsunamoto, K., Ludwig, R. & Schwab, M. (1990) Cancer Res. 50, 4411-4416.2364393 / Cancer Res. (1990)
Lutz, W., Stohr, M., Schurmann, J., Wenzel, A., Lohr, A. & Schwab, M. (1996) Oncogene 13, 803-812.8761302 / Oncogene (1996)
10.1146/annurev.cellbio.16.1.653
10.1038/sj.onc.1202725
10.1038/sj.onc.1202746
10.1073/pnas.96.7.3940
10.1016/S0304-3835(03)00103-4
10.1046/j.1432-1327.1999.00575.x
10.1016/0006-291X(91)91735-U
10.1016/j.gene.2003.09.042
10.1038/sj.onc.1207261
10.1002/1097-0142(19940615)73:12<3087::AID-CNCR2820731230>3.0.CO;2-9
Vogan, K., Bernstein, M., Leclerc, J. M., Brisson, L., Brossard, J., Brodeur, G. M., Pelletier, J. & Gros, P. (1993) Cancer Res. 53, 5269-5273.8221661 / Cancer Res. (1993)
Tonelli R. Fronza R. Purgato S. Camerin C. Bolgna F. Alboresi S. Franzoni M. Corradini R. Sforza S. Faccini A. et al . (2004) Mol. Cancer Ther. in press.
10.1074/jbc.M300771200
10.1016/S1046-2023(02)00007-5
10.1016/S1046-2023(02)00006-3
10.1128/MCB.22.3.856-865.2002
10.1002/1098-2744(200010)29:2<76::AID-MC4>3.0.CO;2-Y
10.1093/nar/23.14.2584
10.1038/sj.onc.1202949
Phelps, M., Darley, M., Primrose, J. N. & Blaydes, J. P. (2003) Cancer Res. 63, 2616-2623.12750288 / Cancer Res. (2003)
Pession, A., Tonelli, R., Fronza, R., Sciamanna, E., Corradini, R., Sforza, S., Tedeschi, T., Marchelli, R., Montanaro, L., Camerin, C., et al. (2004) Int. J. Oncol. 24, 265-272.14719101 / Int. J. Oncol. (2004)
Nielsen, P. E., Pellestor, F., Paulasova, P. & Koppelhus, U. (2005) Methods Mol. Biol. 288, 343-358.15333914 / Methods Mol. Biol. (2005)
10.1038/sj.ejhg.5201226
10.1016/S0378-1119(99)00487-4
Moll, U. M. & Petrenko, O. (2003) Mol. Cancer Res. 1, 1001-1008.14707283 / Mol. Cancer Res. (2003)
10.1074/jbc.M312264200
Ganguli, G. & Wasylyk, B. (2003) Mol. Cancer Res. 1, 1027-1035.14707286 / Mol. Cancer Res. (2003)
Deb, S. P. (2003) Mol. Cancer Res. 1, 1009-1016.14707284 / Mol. Cancer Res. (2003)
Meek, D. W. & Knippschild, U. (2003) Mol. Cancer Res. 1, 1017-1026.14707285 / Mol. Cancer Res. (2003)
Onel, K. & Cordon-Cardo, C. (2004) Mol. Cancer Res. 2, 1-8.14757840 (10.1158/1541-7786.1.2.1) / Mol. Cancer Res. (2004)
10.1038/sj.onc.1206985
10.1128/MCB.21.22.7653-7662.2001
10.1128/MCB.22.5.1360-1368.2002
10.1093/emboj/cdg133
10.1101/gad.1067003
10.1073/pnas.83.6.1772
Zimmerman, K. & Alt, F. W. (1990) Crit. Rev. Oncog. 2, 75-95.2091750 / Crit. Rev. Oncog. (1990)
10.1038/318533a0
10.1101/gad.13.20.2658
Knudson, C. M., Johnson, G. M., Lin, Y. & Korsmeyer, S. J. (2001) Cancer Res. 61, 659-665.11212265 / Cancer Res. (2001)
10.1128/MCB.21.15.5063-5070.2001
10.1073/pnas.0401083101
10.1126/science.1092472

Dates

Type	When
Created	20 years, 7 months ago (Jan. 11, 2005, 10:13 p.m.)
Deposited	2 years, 3 months ago (May 1, 2023, 9:53 a.m.)
Indexed	1 month ago (July 16, 2025, 8:48 a.m.)
Issued	20 years, 7 months ago (Jan. 11, 2005)
Published	20 years, 7 months ago (Jan. 11, 2005)
Published Online	20 years, 7 months ago (Jan. 11, 2005)
Published Print	20 years, 7 months ago (Jan. 18, 2005)

Funders 0

None

BibTeX

@article{Slack_2005, title={The p53 regulatory geneMDM2is a direct transcriptional target of MYCN in neuroblastoma}, volume={102}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0405495102}, DOI={10.1073/pnas.0405495102}, number={3}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Slack, Andrew and Chen, Zaowen and Tonelli, Roberto and Pule, Martin and Hunt, Lisa and Pession, Andrea and Shohet, Jason M.}, year={2005}, month=jan, pages={731–736} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        7,
        16
      ]
    ],
    "date-time": "2025-07-16T12:48:51Z",
    "timestamp": 1752670131057
  },
  "reference-count": 48,
  "publisher": "Proceedings of the National Academy of Sciences",
  "issue": "3",
  "content-domain": {
    "domain": [
      "www.pnas.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2005,
        1,
        18
      ]
    ]
  },
  "abstract": "<jats:p>The<jats:italic>MYCN</jats:italic>oncogene is the major negative prognostic marker in neuroblastoma with important roles in both the pathogenesis and clinical behavior of this aggressive malignancy.<jats:italic>MYC</jats:italic>oncogenes activate both proliferative and apoptotic cellular pathways and, accordingly, inhibition of p53-mediated apoptosis is a prerequisite for MYC-driven tumorigenesis. To identify novel transcriptional targets mediating the MYCN-dependent phenotype, we screened a MYCN-amplified neuroblastoma cell line by using chromatin immunoprecipitation (ChIP) cloning. We identified the essential p53 inhibitor and protooncogene<jats:italic>MDM2</jats:italic>as a putative target. MDM2 has multiple p53-independent functions modulating cell cycle and transcriptional events. Standard ChIP with MYCN antibodies established the binding of MYCN to a consensus E-box within the human<jats:italic>MDM2</jats:italic>promoter. Oligonucleotide pull-down assays further established the capacity of MYCN to bind to this promoter region, confirming the ChIP results. Luciferase reporter assays confirmed the E-box-specific, MYCN-dependent regulation of the<jats:italic>MDM2</jats:italic>promoter in MYCN-inducible neuroblastoma cell lines. Real-time quantitative PCR and Western blot analysis demonstrated a rapid increase in endogenous<jats:italic>MDM2</jats:italic>mRNA and MDM2 protein upon induction of MYCN. Targeted inhibition of MYCN in a<jats:italic>MYCN</jats:italic>-amplified neuroblastoma cell line resulted in decreased MDM2 expression levels with concomitant stabilization of p53 and induction of apoptosis. Our finding that MYCN directly modulates baseline MDM2 levels suggests a mechanism contributing to the pathogenesis of neuroblastoma and other MYC-driven malignancies through inhibition of MYC-stimulated apoptosis.</jats:p>",
  "DOI": "10.1073/pnas.0405495102",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2005,
        1,
        12
      ]
    ],
    "date-time": "2005-01-12T03:13:35Z",
    "timestamp": 1105499615000
  },
  "page": "731-736",
  "update-policy": "http://dx.doi.org/10.1073/pnas.cm10313",
  "source": "Crossref",
  "is-referenced-by-count": 188,
  "title": "The p53 regulatory gene<i>MDM2</i>is a direct transcriptional target of MYCN in neuroblastoma",
  "prefix": "10.1073",
  "volume": "102",
  "author": [
    {
      "given": "Andrew",
      "family": "Slack",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Center for Cell and Gene Therapy, Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Street, Houston, TX 77030, and Department of Pediatrics, University of Bologna, Santa Orsola Hospital, Via Massarenti, 11-40138 Bologna, Italy"
        }
      ]
    },
    {
      "given": "Zaowen",
      "family": "Chen",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Center for Cell and Gene Therapy, Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Street, Houston, TX 77030, and Department of Pediatrics, University of Bologna, Santa Orsola Hospital, Via Massarenti, 11-40138 Bologna, Italy"
        }
      ]
    },
    {
      "given": "Roberto",
      "family": "Tonelli",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Center for Cell and Gene Therapy, Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Street, Houston, TX 77030, and Department of Pediatrics, University of Bologna, Santa Orsola Hospital, Via Massarenti, 11-40138 Bologna, Italy"
        }
      ]
    },
    {
      "given": "Martin",
      "family": "Pule",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Center for Cell and Gene Therapy, Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Street, Houston, TX 77030, and Department of Pediatrics, University of Bologna, Santa Orsola Hospital, Via Massarenti, 11-40138 Bologna, Italy"
        }
      ]
    },
    {
      "given": "Lisa",
      "family": "Hunt",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Center for Cell and Gene Therapy, Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Street, Houston, TX 77030, and Department of Pediatrics, University of Bologna, Santa Orsola Hospital, Via Massarenti, 11-40138 Bologna, Italy"
        }
      ]
    },
    {
      "given": "Andrea",
      "family": "Pession",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Center for Cell and Gene Therapy, Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Street, Houston, TX 77030, and Department of Pediatrics, University of Bologna, Santa Orsola Hospital, Via Massarenti, 11-40138 Bologna, Italy"
        }
      ]
    },
    {
      "given": "Jason M.",
      "family": "Shohet",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Center for Cell and Gene Therapy, Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Street, Houston, TX 77030, and Department of Pediatrics, University of Bologna, Santa Orsola Hospital, Via Massarenti, 11-40138 Bologna, Italy"
        }
      ]
    }
  ],
  "member": "341",
  "published-online": {
    "date-parts": [
      [
        2005,
        1,
        11
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_3_2_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1056/NEJM199910143411601"
    },
    {
      "key": "e_1_3_2_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0304-3835(03)00454-3"
    },
    {
      "key": "e_1_3_2_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/emboj/16.11.2985"
    },
    {
      "key": "e_1_3_2_4_2",
      "first-page": "4411",
      "volume": "50",
      "year": "1990",
      "unstructured": "Schweigerer, L., Breit, S., Wenzel, A., Tsunamoto, K., Ludwig, R. & Schwab, M. (1990) Cancer Res. 50, 4411-4416.2364393",
      "journal-title": "Cancer Res."
    },
    {
      "key": "e_1_3_2_5_2",
      "first-page": "803",
      "volume": "13",
      "year": "1996",
      "unstructured": "Lutz, W., Stohr, M., Schurmann, J., Wenzel, A., Lohr, A. & Schwab, M. (1996) Oncogene 13, 803-812.8761302",
      "journal-title": "Oncogene"
    },
    {
      "key": "e_1_3_2_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.cellbio.16.1.653"
    },
    {
      "key": "e_1_3_2_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.onc.1202725"
    },
    {
      "key": "e_1_3_2_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.onc.1202746"
    },
    {
      "key": "e_1_3_2_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.96.7.3940"
    },
    {
      "key": "e_1_3_2_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0304-3835(03)00103-4"
    },
    {
      "key": "e_1_3_2_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1046/j.1432-1327.1999.00575.x"
    },
    {
      "key": "e_1_3_2_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0006-291X(91)91735-U"
    },
    {
      "key": "e_1_3_2_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.gene.2003.09.042"
    },
    {
      "key": "e_1_3_2_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.onc.1207261"
    },
    {
      "key": "e_1_3_2_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/1097-0142(19940615)73:12<3087::AID-CNCR2820731230>3.0.CO;2-9"
    },
    {
      "key": "e_1_3_2_16_2",
      "first-page": "5269",
      "volume": "53",
      "year": "1993",
      "unstructured": "Vogan, K., Bernstein, M., Leclerc, J. M., Brisson, L., Brossard, J., Brodeur, G. M., Pelletier, J. & Gros, P. (1993) Cancer Res. 53, 5269-5273.8221661",
      "journal-title": "Cancer Res."
    },
    {
      "key": "e_1_3_2_17_2",
      "unstructured": "Tonelli R. Fronza R. Purgato S. Camerin C. Bolgna F. Alboresi S. Franzoni M. Corradini R. Sforza S. Faccini A. et al . (2004) Mol. Cancer Ther. in press."
    },
    {
      "key": "e_1_3_2_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M300771200"
    },
    {
      "key": "e_1_3_2_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S1046-2023(02)00007-5"
    },
    {
      "key": "e_1_3_2_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S1046-2023(02)00006-3"
    },
    {
      "key": "e_1_3_2_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/MCB.22.3.856-865.2002"
    },
    {
      "key": "e_1_3_2_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/1098-2744(200010)29:2<76::AID-MC4>3.0.CO;2-Y"
    },
    {
      "key": "e_1_3_2_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/nar/23.14.2584"
    },
    {
      "key": "e_1_3_2_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.onc.1202949"
    },
    {
      "key": "e_1_3_2_25_2",
      "first-page": "2616",
      "volume": "63",
      "year": "2003",
      "unstructured": "Phelps, M., Darley, M., Primrose, J. N. & Blaydes, J. P. (2003) Cancer Res. 63, 2616-2623.12750288",
      "journal-title": "Cancer Res."
    },
    {
      "key": "e_1_3_2_26_2",
      "first-page": "265",
      "volume": "24",
      "year": "2004",
      "unstructured": "Pession, A., Tonelli, R., Fronza, R., Sciamanna, E., Corradini, R., Sforza, S., Tedeschi, T., Marchelli, R., Montanaro, L., Camerin, C., et al. (2004) Int. J. Oncol. 24, 265-272.14719101",
      "journal-title": "Int. J. Oncol."
    },
    {
      "key": "e_1_3_2_27_2",
      "first-page": "343",
      "volume": "288",
      "year": "2005",
      "unstructured": "Nielsen, P. E., Pellestor, F., Paulasova, P. & Koppelhus, U. (2005) Methods Mol. Biol. 288, 343-358.15333914",
      "journal-title": "Methods Mol. Biol."
    },
    {
      "key": "e_1_3_2_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.ejhg.5201226"
    },
    {
      "key": "e_1_3_2_29_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0378-1119(99)00487-4"
    },
    {
      "key": "e_1_3_2_30_2",
      "first-page": "1001",
      "volume": "1",
      "year": "2003",
      "unstructured": "Moll, U. M. & Petrenko, O. (2003) Mol. Cancer Res. 1, 1001-1008.14707283",
      "journal-title": "Mol. Cancer Res."
    },
    {
      "key": "e_1_3_2_31_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M312264200"
    },
    {
      "key": "e_1_3_2_32_2",
      "first-page": "1027",
      "volume": "1",
      "year": "2003",
      "unstructured": "Ganguli, G. & Wasylyk, B. (2003) Mol. Cancer Res. 1, 1027-1035.14707286",
      "journal-title": "Mol. Cancer Res."
    },
    {
      "key": "e_1_3_2_33_2",
      "first-page": "1009",
      "volume": "1",
      "year": "2003",
      "unstructured": "Deb, S. P. (2003) Mol. Cancer Res. 1, 1009-1016.14707284",
      "journal-title": "Mol. Cancer Res."
    },
    {
      "key": "e_1_3_2_34_2",
      "first-page": "1017",
      "volume": "1",
      "year": "2003",
      "unstructured": "Meek, D. W. & Knippschild, U. (2003) Mol. Cancer Res. 1, 1017-1026.14707285",
      "journal-title": "Mol. Cancer Res."
    },
    {
      "key": "e_1_3_2_35_2",
      "doi-asserted-by": "crossref",
      "first-page": "1",
      "DOI": "10.1158/1541-7786.1.2.1",
      "volume": "2",
      "year": "2004",
      "unstructured": "Onel, K. & Cordon-Cardo, C. (2004) Mol. Cancer Res. 2, 1-8.14757840",
      "journal-title": "Mol. Cancer Res."
    },
    {
      "key": "e_1_3_2_36_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.onc.1206985"
    },
    {
      "key": "e_1_3_2_37_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/MCB.21.22.7653-7662.2001"
    },
    {
      "key": "e_1_3_2_38_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/MCB.22.5.1360-1368.2002"
    },
    {
      "key": "e_1_3_2_39_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/emboj/cdg133"
    },
    {
      "key": "e_1_3_2_40_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1101/gad.1067003"
    },
    {
      "key": "e_1_3_2_41_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.83.6.1772"
    },
    {
      "key": "e_1_3_2_42_2",
      "first-page": "75",
      "volume": "2",
      "year": "1990",
      "unstructured": "Zimmerman, K. & Alt, F. W. (1990) Crit. Rev. Oncog. 2, 75-95.2091750",
      "journal-title": "Crit. Rev. Oncog."
    },
    {
      "key": "e_1_3_2_43_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/318533a0"
    },
    {
      "key": "e_1_3_2_44_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1101/gad.13.20.2658"
    },
    {
      "key": "e_1_3_2_45_2",
      "first-page": "659",
      "volume": "61",
      "year": "2001",
      "unstructured": "Knudson, C. M., Johnson, G. M., Lin, Y. & Korsmeyer, S. J. (2001) Cancer Res. 61, 659-665.11212265",
      "journal-title": "Cancer Res."
    },
    {
      "key": "e_1_3_2_46_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/MCB.21.15.5063-5070.2001"
    },
    {
      "key": "e_1_3_2_47_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.0401083101"
    },
    {
      "key": "e_1_3_2_48_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.1092472"
    }
  ],
  "container-title": "Proceedings of the National Academy of Sciences",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://pnas.org/doi/pdf/10.1073/pnas.0405495102",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2023,
        5,
        1
      ]
    ],
    "date-time": "2023-05-01T13:53:36Z",
    "timestamp": 1682949216000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://pnas.org/doi/full/10.1073/pnas.0405495102"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2005,
        1,
        11
      ]
    ]
  },
  "references-count": 48,
  "journal-issue": {
    "issue": "3",
    "published-print": {
      "date-parts": [
        [
          2005,
          1,
          18
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1073/pnas.0405495102"
  ],
  "URL": "http://dx.doi.org/10.1073/pnas.0405495102",
  "relation": {},
  "ISSN": [
    "0027-8424",
    "1091-6490"
  ],
  "subject": [],
  "container-title-short": "Proc. Natl. Acad. Sci. U.S.A.",
  "published": {
    "date-parts": [
      [
        2005,
        1,
        11
      ]
    ]
  },
  "assertion": [
    {
      "value": "2004-07-28",
      "order": 0,
      "name": "received",
      "label": "Received",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2004-11-19",
      "order": 1,
      "name": "accepted",
      "label": "Accepted",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2005-01-11",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}