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.

Role of Mdm4 in drug sensitivity of breast cancer cells

“…Therefore, despite strong similarities between the p53-binding domains of Mdm4 and Mdm2, minor differences are sufficient to reduce the inhibitory effect of Nutlin-3 on Mdm4-p53 binding. Consistently, some studies have suggested that Mdm4 levels determine the sensitivity of tumor cells for anticancer therapy (Hu et al, 2006;Laurie et al, 2006;Patton et al, 2006;Wade et al, 2006).…”

“…In addition, it has been reported that Mdm4 can enhance Mdm2-mediated ubiquitination and degradation of p53 (Stad et al, 2000. Similar to Mdm2, Mdm4 has been found overexpressed in a significant number of various human tumors and tumor cell lines, in general correlating with the expression of wild-type p53, suggesting that Mdm4 contributes to p53 inactivation during tumorigenesis (Riemenschneider et al, 1999(Riemenschneider et al, , 2003Ramos et al, 2001;Danovi et al, 2004;Laurie et al, 2006). As both Mdm2 and Mdm4 are overexpressed in many tumors that retain wild-type p53, they are attractive targets for the development of anti-cancer agents.…”

“…Nutlin-3 was identified based on its ability to inhibit Mdm2-p53 binding. The p53-binding pockets of Mdm2 and Mdm4 show high homology and it has been shown that Nutlin-3 was able to disrupt the binding between Mdm4 and p53 by binding to Mdm4 (Laurie et al, 2006), although conflicting results have been reported (Hu et al, 2006;Patton et al, 2006;Wade et al, 2006). Similarly, MI-219 activates p53 by disrupting the Mdm2-p53 interaction.…”

Réactivation de p53 dans les tumeurs : une stratégie antitumorale prometteuse

“…Un autre acteur majeur de cette voie de régulation est MDM4 (aussi connu sous le nom de MDMX). MDM4 est un inhibiteur spéci-fique de p53 qui est amplifié ou surexprimé dans 10 à 20 % des cancers [1], et jusqu'à 65 % des cas de rétinoblasto-mes [7]. MDM4 partage des similitudes structurales avec MDM2.…”

“…Cependant, il ne contrôle pas la stabilité de p53, mais son activité transcriptionnelle [8,9] (Figure 1 [1,7] (Figure 1). La recherche d'antagonistes de MDM4 plus efficaces est un objectif clinique important, puisque l'inhibition spécifique de MDM4 dans les cellules tumorales limite la croissance des tumeurs xénogreffées [7,8] Certaines données suggéraient une sensibilité accrue des cellules tumorales à la Nutlin du fait d'une altération de leur transcriptome [11], mais d'autres montraient que l'inactivation totale de MDM2 dans des cellules normales est rapidement létale chez la souris [12]. Trois nouveaux modèles murins apportent maintenant des informations cruciales sur ces points et révèlent également des informations inattendues.…”