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

doi:10.1038/nature05194

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

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519 Scopus citations

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 language	English
Pages (from-to)	61-66
Number of pages	6
Journal	Nature
Volume	444
Issue number	7115
DOIs	https://doi.org/10.1038/nature05194
State	Published - Nov 2 2006

Bibliographical note

Funding Information:
Acknowledgements We thank L. Harris, G. Zambetti and M. Baron for discussions; S. Pounds for statistical analysis; M. Roussel for MDMX and MDM2 retroviruses; B. Schulman and D. Bashford for assistance with MDMX–-nutlin-3 modelling; A. McArthur for editorial assistance; J. Gray for assistance with real-time RT–-PCR and genomic DNA preparations; and F. Carlotti and M. Rabeling for advice on lentiviral experiments and production of lentivirus stocks. This work was supported by grants (to M.A.D.) from the National Eye Institute, Cancer Center Support from the National Cancer Institute, the American Cancer Society, Research to Prevent Blindness, the Pearle Vision Foundation, the International Retinal Research Foundation and the American Lebanese Syrian Associated Charities (ALSAC). M.A.D. is a Pew Scholar. This work was also supported by funding from the Association for International Cancer Research (A.G.J.) and EC FP6 (A.G.J. and J.-C.M.), the Dutch Cancer Society (Y.R.), the Belgian Foundation against Cancer (J.-C.M.) and Télévie (S.F.). This publication was supported in part by a grant from the National Cancer Institute.

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Laurie, N. A., Donovan, S. L., 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, S. M., Guy, R. K., Marine, J. C., Jochemsen, A. G., & Dyer, M. A. (2006). Inactivation of the p53 pathway in retinoblastoma. Nature, 444(7115), 61-66. https://doi.org/10.1038/nature05194

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title = "Inactivation of the p53 pathway in retinoblastoma",

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.",

author = "Laurie, {Nikia A.} and Donovan, {Stacy L.} and Shih, {Chie Schin} and Jiakun Zhang and Nicholas Mills and Christine Fuller and Amina Teunisse and Suzanne Lam and Yolande Ramos and Adithi Mohan and Dianna Johnson and Matthew Wilson and Carlos Rodriguez-Galindo and Micaela Quarto and Sarah Francoz and Mendrysa, {Susan M.} and Guy, {R. Kiplin} and Marine, {Jean Christophe} and Jochemsen, {Aart G.} and Dyer, {Michael A.}",

note = "Funding Information: Acknowledgements We thank L. Harris, G. Zambetti and M. Baron for discussions; S. Pounds for statistical analysis; M. Roussel for MDMX and MDM2 retroviruses; B. Schulman and D. Bashford for assistance with MDMX–-nutlin-3 modelling; A. McArthur for editorial assistance; J. Gray for assistance with real-time RT–-PCR and genomic DNA preparations; and F. Carlotti and M. Rabeling for advice on lentiviral experiments and production of lentivirus stocks. This work was supported by grants (to M.A.D.) from the National Eye Institute, Cancer Center Support from the National Cancer Institute, the American Cancer Society, Research to Prevent Blindness, the Pearle Vision Foundation, the International Retinal Research Foundation and the American Lebanese Syrian Associated Charities (ALSAC). M.A.D. is a Pew Scholar. This work was also supported by funding from the Association for International Cancer Research (A.G.J.) and EC FP6 (A.G.J. and J.-C.M.), the Dutch Cancer Society (Y.R.), the Belgian Foundation against Cancer (J.-C.M.) and T{\'e}l{\'e}vie (S.F.). This publication was supported in part by a grant from the National Cancer Institute.",

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AU - Laurie, Nikia A.

AU - Donovan, Stacy L.

AU - Shih, Chie Schin

AU - Zhang, Jiakun

AU - Mills, Nicholas

AU - Fuller, Christine

AU - Teunisse, Amina

AU - Lam, Suzanne

AU - Ramos, Yolande

AU - Mohan, Adithi

AU - Johnson, Dianna

AU - Wilson, Matthew

AU - Rodriguez-Galindo, Carlos

AU - Quarto, Micaela

AU - Francoz, Sarah

AU - Mendrysa, Susan M.

AU - Guy, R. Kiplin

AU - Marine, Jean Christophe

AU - Jochemsen, Aart G.

AU - Dyer, Michael A.

N1 - Funding Information: Acknowledgements We thank L. Harris, G. Zambetti and M. Baron for discussions; S. Pounds for statistical analysis; M. Roussel for MDMX and MDM2 retroviruses; B. Schulman and D. Bashford for assistance with MDMX–-nutlin-3 modelling; A. McArthur for editorial assistance; J. Gray for assistance with real-time RT–-PCR and genomic DNA preparations; and F. Carlotti and M. Rabeling for advice on lentiviral experiments and production of lentivirus stocks. This work was supported by grants (to M.A.D.) from the National Eye Institute, Cancer Center Support from the National Cancer Institute, the American Cancer Society, Research to Prevent Blindness, the Pearle Vision Foundation, the International Retinal Research Foundation and the American Lebanese Syrian Associated Charities (ALSAC). M.A.D. is a Pew Scholar. This work was also supported by funding from the Association for International Cancer Research (A.G.J.) and EC FP6 (A.G.J. and J.-C.M.), the Dutch Cancer Society (Y.R.), the Belgian Foundation against Cancer (J.-C.M.) and Télévie (S.F.). This publication was supported in part by a grant from the National Cancer Institute.

PY - 2006/11/2

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N2 - 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.

AB - 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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Inactivation of the p53 pathway in retinoblastoma

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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