Functional Cooperation of RKTG with p53 in Tumorigenesis and Epithelial-Mesenchymal Transition
Functional Cooperation of RKTG with p53 in Tumorigenesis and Epithelial-Mesenchymal Transition
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RKTG 与 p53 在肿瘤发生和上皮间质转化中的功能合作
DOI：
10.1158/0008-5472.can-10-4077
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Chen, Yan
中科院分区：
文献类型：
--
作者：
Jiang, Yuhui;Xie, Xiaoduo;Chen, Yan
Raf kinase trapping to Golgi （RKTG）是一种潜在的肿瘤抑制基因，它在调节Ras/Raf/MEK/ERK（胞外信号调节激酶）通路和GPCR （G蛋白偶联受体）G β - γ亚基信号通路中起负作用。有趣的是，缺乏rktg的小鼠没有肿瘤，尽管它们在服用致癌物后容易形成皮肤癌。另一方面，p53是一种特征明显的肿瘤抑制基因，p53杂合小鼠从12个月大开始发生肉瘤和其他肿瘤。在rktg缺失的小鼠胚胎成纤维细胞中，脂磷脂酸（LPA），而不是表皮生长因子（EGF），可以刺激AKT和GSK3 β的过度磷酸化，同时p53的Ser15位点磷酸化增加，p53及其靶基因p21和p16的积累。在7月龄的RKTG无合子和p53杂合子小鼠中，约25%检测到自发性皮肤癌样肿瘤。肿瘤覆盖表皮出现增生和上皮间质转化（epithelial-mesenchymal transition， EMT），其中p53发生LOH， EMT特征出现。在p53突变的A431上皮癌细胞中，RKTG的下调导致lpa刺激的AKT和GSK3 β磷酸化增强，同时β -连环蛋白的积累增加，并出现被p53过表达拮抗的EMT特征。在HepG2上皮细胞中，当RKTG和p53同时被沉默时，lpa刺激的AKT磷酸化和EMT特征达到最大。综上所述，这些结果不仅表明RKTG在体内具有协同p53的抑瘤功能，而且表明p53具有EMT检查点功能，该功能的缺失可与RKTG的缺失联合驱动EMT和肿瘤进展。癌症Res;71 (8);2959 - 68。AACR (C) 2011。
Raf kinase trapping to Golgi (RKTG) is a potential tumor suppressor gene due to its negative roles in regulating Ras/Raf/MEK/ERK (extracellular signal-regulated kinase) pathway and GPCR (G protein-coupled receptor) G beta gamma subunit signaling. Interestingly, RKTG-deficient mice are free of tumors, although they are prone to form skin cancer on carcinogen administration. On the other hand, p53 is a well-characterized tumor suppressor gene and p53 heterozygous mice develop sarcoma and other tumors starting from 12 months of age. In RKTG-null mouse embryonic fibroblasts, lypophosphatidic acid (LPA), but not EGF (epidermal growth factor), could stimulate hyperphosphorylation of AKT and GSK3 beta, accompanied by increases in phosphorylation of p53 at Ser15 and accumulation of p53, as well as its target genes p21 and p16. Spontaneous skin cancer-like tumors were detected in about 25% of RKTG nullizygous and p53 heterozygous mice within 7 months of age. Hyperplasia and epithelial-mesenchymal transition (EMT) were observed in the tumor-overlying epidermis, in which LOH of p53 occurred and EMT features emerged. In p53-mutated A431 epithelial carcinoma cells, knockdown of RKTG led to enhancement of LPA-stimulated AKT and GSK3 beta phosphorylation, together with increased accumulation of beta-catenin and appearance of EMT features that were antagonized by p53 overexpression. In HepG2 epithelial cells, LPA-stimulated AKT phosphorylation and EMT features reached maximum when both RKTG and p53 were simultaneously silenced. In summary, these results not only indicate that RKTG has an in vivo tumor suppressor function to cooperate with p53 in tumorigenesis but also suggest that p53 has an EMT checkpoint function and the loss of this function can combine with loss of RKTG to drive EMT and tumor progression. Cancer Res; 71(8); 2959-68. (C)2011 AACR.