Inactivation of the p53 pathway in retinoblastoma
Inactivation of the p53 pathway in retinoblastoma
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DOI：
10.1038/nature05194
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发表时间：
2006-11-02
期刊：
影响因子：
64.8
通讯作者：
Dyer, Michael A.
中科院分区：
文献类型：
--
作者：
Laurie, Nikia A.;Donovan, Stacy L.;Dyer, Michael A.
大多数人类肿瘤在Rb和p53通路上都有基因突变，但视网膜母细胞瘤被认为是一个例外。研究表明，视网膜母细胞瘤起源于视网膜母细胞瘤1 （RB1）基因突变，绕过p53通路，因为它们是由视网膜发育过程中固有的抗死亡细胞产生的。与这一流行理论相反，本研究表明，由Arf、MDM2、MDMX和p53介导的肿瘤监测途径在视网膜形成过程中RB1缺失后被激活。缺乏rb1的视网膜母细胞经历p53介导的凋亡并退出细胞周期。随后，在肿瘤进展过程中，MDMX基因的扩增和MDMX蛋白的表达增加被强烈选择为抑制rb1缺陷视网膜细胞中p53反应的机制。我们的数据提供了证据，证明p53通路在视网膜母细胞瘤中失活，并且这种癌症并不像以前认为的那样起源于固有的抗死亡细胞。此外，他们支持MDMX是治疗视网膜母细胞瘤的特定化疗靶点的观点。
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.