Tissue-specific p19Arf regulation dictates the response to oncogenic K-ras
Tissue-specific p19Arf regulation dictates the response to oncogenic K-ras
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DOI：
10.1073/pnas.1004796107
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发表时间：
2010-06-01
影响因子：
11.1
通讯作者：
Jacks, Tyler
中科院分区：
文献类型：
--
作者：
Young, Nathan P.;Jacks, Tyler
癌基因参与肿瘤抑制途径的能力代表了一种关键的调节机制，可以限制早期肿瘤细胞的生长。例如，在许多情况下，致癌Ras强烈激活Ink4a/Arf基因座，导致细胞周期停滞或衰老。不同类型的细胞在体内表达内源性K-ras（G12D）后执行肿瘤抑制程序的能力尚未得到研究。使用含有Arf（GFP）报告基因和自发激活K-ras（LA2）等位基因的复合突变小鼠，我们发现了K-ras（G12D）依赖性p19（Arf）上调的显著组织特异性。肺肿瘤，可以出现在功能性p19（Arf）的存在下，很少显示p19（Arf）诱导。相反，肉瘤总是表现出强烈的激活，这与遗传证据相关，表明p19（Arf）-p53通路的丢失是肉瘤发生的必要事件。使用组成型和诱导型RNAi系统在体内，我们强调细胞类型特异性染色质调控的Ink4a/Arf作为一个关键的决定因素的细胞反应致癌K-ras。多梳组复合物抑制肺癌的基因座，而SWI/SNF家族成员Snf5作为肉瘤中p19（Arf）诱导的重要介质。肿瘤抑制诱导的这种变化可能解释了组织对Ras介导的转化的敏感性的固有差异。
The ability of oncogenes to engage tumor suppressor pathways represents a key regulatory mechanism that can limit the outgrowth of incipient tumor cells. For example, in a number of settings oncogenic Ras strongly activates the Ink4a/Arf locus, resulting in cell cycle arrest or senescence. The capacity of different cell types to execute tumor suppressor programs following expression of endogenous K-ras(G12D) in vivo has not been examined. Using compound mutant mice containing the Arf(GFP) reporter and the spontaneously activating K-ras(LA2) allele, we have uncovered dramatic tissue specificity of K-ras(G12D)-dependent p19(Arf) up-regulation. Lung tumors, which can arise in the presence of functional p19(Arf), rarely display p19(Arf) induction. In contrast, sarcomas always show robust activation, which correlates with genetic evidence, suggesting that loss of the p19(Arf)-p53 pathway is a requisite event for sarcomagenesis. Using constitutive and inducible RNAi systems in vivo, we highlight cell type-specific chromatin regulation of Ink4a/Arf as a critical determinant of cellular responses to oncogenic K-ras. Polycomb-group complexes repress the locus in lung tumors, whereas the SWI/SNF family member Snf5 acts as an important mediator of p19(Arf) induction in sarcomas. This variation in tumor suppressor induction might explain the inherent differences between tissues in their sensitivity to Ras-mediated transformation.