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, Michael A. Dyer

Research output: Contribution to journalArticle

429 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)61-66
Number of pages6
JournalNature
Volume444
Issue number7115
DOIs
StatePublished - Nov 2 2006
Externally publishedYes

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Retinoblastoma
Neoplasms
Cell Death
Proto-Oncogene Proteins c-mdm2
Retinoblastoma Genes
Mutation
Cell Cycle
Apoptosis
Gene Expression

ASJC Scopus subject areas

  • General

Cite this

Laurie, N. A., Donovan, S. L., Shih, C-S., Zhang, J., Mills, N., Fuller, C., ... Dyer, M. A. (2006). Inactivation of the p53 pathway in retinoblastoma. Nature, 444(7115), 61-66. https://doi.org/10.1038/nature05194

Inactivation of the p53 pathway in retinoblastoma. / Laurie, Nikia A.; Donovan, Stacy L.; Shih, Chie-Schin; Zhang, Jiakun; Mills, Nicholas; Fuller, Christine; Teunisse, Amina; Lam, Suzanne; Ramos, Yolande; Mohan, Adithi; Johnson, Dianna; Wilson, Matthew; Rodriguez-Galindo, Carlos; Quarto, Micaela; Francoz, Sarah; Mendrysa, Susan M.; Guy, R. Kiplin; Marine, Jean Christophe; Jochemsen, Aart G.; Dyer, Michael A.

In: Nature, Vol. 444, No. 7115, 02.11.2006, p. 61-66.

Research output: Contribution to journalArticle

Laurie, NA, Donovan, SL, Shih, C-S, Zhang, J, Mills, N, Fuller, C, Teunisse, A, Lam, S, Ramos, Y, Mohan, A, Johnson, D, Wilson, M, Rodriguez-Galindo, C, Quarto, M, Francoz, S, Mendrysa, SM, Guy, RK, Marine, JC, Jochemsen, AG & Dyer, MA 2006, 'Inactivation of the p53 pathway in retinoblastoma', Nature, vol. 444, no. 7115, pp. 61-66. https://doi.org/10.1038/nature05194
Laurie NA, Donovan SL, Shih C-S, Zhang J, Mills N, Fuller C et al. Inactivation of the p53 pathway in retinoblastoma. Nature. 2006 Nov 2;444(7115):61-66. https://doi.org/10.1038/nature05194
Laurie, Nikia A. ; Donovan, Stacy L. ; Shih, Chie-Schin ; Zhang, Jiakun ; Mills, Nicholas ; Fuller, Christine ; Teunisse, Amina ; Lam, Suzanne ; Ramos, Yolande ; Mohan, Adithi ; Johnson, Dianna ; Wilson, Matthew ; Rodriguez-Galindo, Carlos ; Quarto, Micaela ; Francoz, Sarah ; Mendrysa, Susan M. ; Guy, R. Kiplin ; Marine, Jean Christophe ; Jochemsen, Aart G. ; Dyer, Michael A. / Inactivation of the p53 pathway in retinoblastoma. In: Nature. 2006 ; Vol. 444, No. 7115. pp. 61-66.
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