Compensation by tumor suppressor genes during retinal development in mice and humans
Compensation by tumor suppressor genes during retinal development in mice and humans
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DOI：
10.1186/1741-7007-4-14
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发表时间：
2006-05-03
期刊：
影响因子：
5.4
通讯作者：
Dyer, Michael A.
中科院分区：
文献类型：
--
作者：
Donovan, Stacy L.;Schweers, Brett;Dyer, Michael A.
背景：RB1基因是通过研究视网膜母细胞瘤家系的遗传损伤而从人类中克隆的第一个肿瘤抑制基因。遗传一个RB1基因缺陷拷贝的儿童患视网膜母细胞瘤的易感性增加。在鉴定出人类RB1基因几年后，在小鼠身上产生了Rb的靶向缺失。携带一个Rb基因缺陷拷贝的小鼠不会患上视网膜母细胞瘤。在这篇论文中，我们探讨了Rb家族在人和小鼠视网膜发育中的不同作用，以更好地了解视网膜母细胞瘤易感性的物种差异。结果：我们发现Rb家族蛋白(Rb、p107和p130)在小鼠视网膜发育过程中以动态方式表达。在小鼠胚胎视网膜祖细胞增殖中表达的主要Rb家族成员是p107，它是视网膜形成过程中适当的细胞周期退出所必需的。Rb家族的主要成员是Rb，主要表达于生后增殖的视网膜祖细胞。P130蛋白与Rb在小鼠视网膜内核层和节细胞层的有丝分裂后细胞中冗余表达。当Rb在小鼠视网膜发育过程中以急性或慢性方式失活时，p107以代偿性方式上调。类似地，当p107在小鼠视网膜失活时，Rb表达上调。在发育中的小鼠视网膜中，当p107和/或Rb失活时，p130的表达没有变化。在人类视网膜中，RB1是整个发育过程中表达的主要家族成员。在发育中的人视网膜中几乎没有p107的表达。与发育中的小鼠视网膜相比，当Rb在发育中的人胚胎视网膜中急剧失活时，p107没有以补偿的方式上调。结论：我们认为Rb和p107之间的内在遗传补偿可以防止Rb或p107缺陷小鼠的视网膜母细胞瘤，但这种补偿在人类中不存在。综上所述，这些数据提出了一个模型，解释了为什么人类在RB1缺失后容易患上视网膜母细胞瘤，而小鼠需要Rb和p107基因失活。
Background: The RB1 gene was the first tumor suppressor gene cloned from humans by studying genetic lesions in families with retinoblastoma. Children who inherit one defective copy of the RB1 gene have an increased susceptibility to retinoblastoma. Several years after the identification of the human RB1 gene, a targeted deletion of Rb was generated in mice. Mice with one defective copy of the Rb gene do not develop retinoblastoma. In this manuscript, we explore the different roles of the Rb family in human and mouse retinal development in order to better understand the species-specific difference in retinoblastoma susceptibility.Results: We found that the Rb family of proteins ( Rb, p107 and p130) are expressed in a dynamic manner during mouse retinal development. The primary Rb family member expressed in proliferating embryonic retinal progenitor cells in mice is p107, which is required for appropriate cell cycle exit during retinogenesis. The primary Rb family member expressed in proliferating postnatal retinal progenitor cells is Rb. p130 protein is expressed redundantly with Rb in postmitotic cells of the inner nuclear layer and the ganglion cell layer of the mouse retina. When Rb is inactivated in an acute or chronic manner during mouse retinal development, p107 is upregulated in a compensatory manner. Similarly, when p107 is inactivated in the mouse retina, Rb is upregulated. No changes in p130 expression were seen when p107, Rb or both were inactivated in the developing mouse retina. In the human retina, RB1 was the primary family member expressed throughout development. There was very little if any p107 expressed in the developing human retina. In contrast to the developing mouse retina, when RB1 was acutely inactivated in the developing human fetal retina, p107 was not upregulated in a compensatory manner.Conclusion: We propose that intrinsic genetic compensation between Rb and p107 prevents retinoblastoma in Rb- or p107-deficient mice, but this compensation does not occur in humans. Together, these data suggest a model that explains why humans are susceptible to retinoblastoma following RB1 loss, but mice require both Rb and p107 gene inactivation.