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
Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Nature. 2006 Nov 2;444(7115):61-6. doi: 10.1038/nature05194.
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.
大多数人类肿瘤在其Rb和p53信号通路中存在基因突变，但视网膜母细胞瘤被认为是个例外。研究表明，由视网膜母细胞瘤1（RB1）基因的突变引发的视网膜母细胞瘤绕过了p53信号通路，因为它们源自视网膜发育过程中内在抗凋亡的细胞。与这一普遍理论相反，我们在此表明，在视网膜生成过程中RB1缺失后，由Arf、MDM2、MDMX和p53介导的肿瘤监测信号通路被激活。RB1缺陷的视网膜母细胞会经历p53介导的凋亡并退出细胞周期。随后，在肿瘤进展过程中，强烈选择MDMX基因的扩增和MDMX蛋白表达的增加，作为抑制RB1缺陷视网膜细胞中p53反应的一种机制。我们的数据提供了证据表明p53信号通路在视网膜母细胞瘤中失活，并且这种癌症并非如先前认为的那样源自内在抗凋亡的细胞。此外，这些数据支持MDMX是治疗视网膜母细胞瘤的一个特定化疗靶点这一观点。
