Genetic interaction between Rb and K-ras in the control of differentiation and tumor suppression
Genetic interaction between Rb and K-ras in the control of differentiation and tumor suppression
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DOI：
10.1128/mcb.24.23.10406-10415.2004
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发表时间：
2004-12-01
影响因子：
5.3
通讯作者：
Ewen, ME
中科院分区：
文献类型：
--
作者：
Takahashi, C;Contreras, B;Ewen, ME
虽然视网膜母细胞瘤蛋白（pRb）已被牵连在细胞分化的过程中，有没有令人信服的遗传或体内证据表明，这样的活动有助于pRb介导的肿瘤抑制。出于细胞培养研究表明，Ras是下游效应的pRb在控制分化，我们研究了Rb和K-ras双敲除小鼠的肿瘤和发育表型。我们发现，K-ras基因的杂合性（i）拯救了一个独特的发育缺陷的子集，其特征是Rb缺陷的胚胎通过影响分化而不是增殖，（ii）显着提高了Rb杂合子中垂体腺癌的分化程度，导致其生存期延长。这些观察结果表明，Rb和K-ras的功能在体内，在胚胎和肿瘤的发展的背景下，并影响分化的能力是一个主要方面的pRb的肿瘤抑制功能。
Although the retinoblastoma protein (pRb) has been implicated in the processes of cellular differentiation, there is no compelling genetic or in vivo evidence that such activities contribute to pRb-mediated tumor suppression. Motivated by cell culture studies suggesting that Ras is a downstream effector of pRb in the control of differentiation, we have examined the tumor and developmental phenotypes of Rb and K-ras double-knockout mice. We find that heterozygosity for K-ras (i) rescued a unique subset of developmental defects that characterize Rb-deficient embryos by affecting differentiation but not proliferation and (ii) significantly enhanced the degree of differentiation of pituitary adenocarcinomas arising in Rb heterozygotes, leading to their prolonged survival. These observations suggest that Rb and K-ras function together in vivo, in the contexts of both embryonic and tumor development, and that the ability to affect differentiation is a major facet of the tumor suppressor function of pRb.