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.
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Nikia A
authors.initials: NA
authors.lastname: Laurie
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Donovan
authors.forename: Chie-Schin
authors.initials: CS
authors.lastname: Shih
authors.forename: Jiakun
authors.initials: J
authors.lastname: Zhang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mills
authors.forename: Christine
authors.initials: C
authors.lastname: Fuller
authors.forename: Amina
authors.initials: A
authors.lastname: Teunisse
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lam
authors.forename: Yolande
authors.initials: Y
authors.lastname: Ramos
authors.forename: Adithi
authors.initials: A
authors.lastname: Mohan
authors.forename: Dianna
authors.initials: D
authors.lastname: Johnson
authors.forename: Matthew
authors.initials: M
authors.lastname: Wilson
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.forename: Micaela
authors.initials: M
authors.lastname: Quarto
authors.forename: Sarah
authors.initials: S
authors.lastname: Francoz
authors.forename: Susan M
authors.initials: SM
authors.lastname: Mendrysa
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.forename: Aart G
authors.initials: AG
authors.lastname: Jochemsen
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D016923:Cell Death; D002455:Cell Division; D004249:DNA Damage; D005784:Gene Amplification / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism; D012175:Retinoblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D007093:Imidazoles; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3