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Inactivation of the p53 pathway in retinoblastoma

Author

Listed:
  • Nikia A. Laurie

    (Department of Developmental Neurobiology)

  • Stacy L. Donovan

    (Department of Developmental Neurobiology)

  • Chie-Schin Shih

    (Department of Developmental Neurobiology)

  • Jiakun Zhang

    (Department of Developmental Neurobiology)

  • Nicholas Mills

    (Department of Chemical Biology and Therapeutics
    Department of Cellular and Molecular Pharmacology, UCSF)

  • Christine Fuller

    (Department of Pathology)

  • Amina Teunisse

    (Leiden University Medical Center)

  • Suzanne Lam

    (Leiden University Medical Center)

  • Yolande Ramos

    (Leiden University Medical Center)

  • Adithi Mohan

    (Department of Developmental Neurobiology)

  • Dianna Johnson

    (University of Tennessee Health Science Center)

  • Matthew Wilson

    (Department of Pathology
    Department of Surgery, Division of Ophthalmology
    University of Tennessee Health Science Center)

  • Carlos Rodriguez-Galindo

    (St Jude Children’s Research Hospital)

  • Micaela Quarto

    (FIRC Institute of Molecular Oncology)

  • Sarah Francoz

    (Flanders Interuniversity Institute for Biotechnology)

  • Susan M. Mendrysa

    (Basic Medical Sciences, Purdue University)

  • R. Kiplin Guy

    (Department of Chemical Biology and Therapeutics)

  • Jean-Christophe Marine

    (Flanders Interuniversity Institute for Biotechnology)

  • Aart G. Jochemsen

    (Leiden University Medical Center)

  • Michael A. Dyer

    (Department of Developmental Neurobiology
    University of Tennessee Health Science Center)

Abstract

Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma.

Suggested Citation

  • Nikia A. Laurie & Stacy L. Donovan & Chie-Schin Shih & Jiakun Zhang & Nicholas Mills & Christine Fuller & Amina Teunisse & Suzanne Lam & Yolande Ramos & Adithi Mohan & Dianna Johnson & Matthew Wilson , 2006. "Inactivation of the p53 pathway in retinoblastoma," Nature, Nature, vol. 444(7115), pages 61-66, November.
    • Handle: RePEc:nat:nature:v:444:y:2006:i:7115:d:10.1038_nature05194
    DOI: 10.1038/nature05194
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    Cited by:

    1. Wesley Tansey & Yixin Wang & Raul Rabadan & David Blei, 2020. "Double Empirical Bayes Testing," International Statistical Review, International Statistical Institute, vol. 88(S1), pages 91-113, December.

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