Inactivation of the p53 pathway in retinoblastoma

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, Carlos Rodriguez-Galindo, Micaela Quarto, Sarah Francoz, Susan M. Mendrysa, R. Kiplin Guy, Jean-Christophe Marine, Aart G. Jochemsen and Michael A. Dyer ()
Additional contact information
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
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
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

Nature, 2006, vol. 444, issue 7115, 61-66

Abstract: 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.

Date: 2006
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DOI: 10.1038/nature05194

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