1. Department of Developmental Neurobiology,
2. Department of Chemical Biology and Therapeutics,
3. Department of Pathology,
4. Department of Surgery, Division of Ophthalmology, and,
5. Department of Hematology–Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
6. Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, California 94143, USA
7. Department of Molecular and Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
8. Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
9. FIRC Institute of Molecular Oncology, 20139 Milan, Italy
10. Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, B-9052 Ghent, Belgium
11. Basic Medical Sciences, Purdue University, West Lafayette, Indiana 47907, USA
12. These authors contributed equally to this work.

Correspondence to: Michael A. Dyer^1,8 Correspondence and requests for materials should be addressed to M.A.D. (Email: michael.dyer@stjude.org).

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.

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