Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Cancer Res. 2011 Apr 15;71(8):2959-68. doi: 10.1158/0008-5472.CAN-10-4077. Epub 2011 Mar 8.
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) Gβγ 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 GSK3β, 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 GSK3β phosphorylation, together with increased accumulation of β-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.
Raf 激酶捕获到高尔基体（RKTG）是一种潜在的肿瘤抑制基因，因为它在调节 Ras/Raf/MEK/ERK（细胞外信号调节激酶）途径和 GPCR（G 蛋白偶联受体）Gβγ亚基信号方面发挥着负面作用。有趣的是，尽管 RKTG 缺陷小鼠在给予致癌剂后容易形成皮肤癌，但它们没有肿瘤。另一方面，p53 是一种特征明确的肿瘤抑制基因，p53 杂合子小鼠从 12 个月大开始就会发展出肉瘤和其他肿瘤。在 RKTG 缺失的小鼠胚胎成纤维细胞中，溶血磷脂酸（LPA）而不是表皮生长因子（EGF）可以刺激 AKT 和 GSK3β的过度磷酸化，伴随着 p53 在 Ser15 处的磷酸化增加和 p53 的积累，以及其靶基因 p21 和 p16。在 7 个月大时，大约 25%的 RKTG 纯合子和 p53 杂合子小鼠中检测到自发性皮肤癌样肿瘤。在肿瘤覆盖的表皮中观察到增生和上皮-间充质转化（EMT），其中发生了 p53 的杂合性丢失并出现了 EMT 特征。在 p53 突变的 A431 上皮癌细胞中，RKTG 的敲低导致 LPA 刺激的 AKT 和 GSK3β磷酸化增强，同时β-catenin 积累增加，并出现 EMT 特征，这些特征被 p53 过表达拮抗。在 HepG2 上皮细胞中，当同时沉默 RKTG 和 p53 时，LPA 刺激的 AKT 磷酸化和 EMT 特征达到最大值。总之，这些结果不仅表明 RKTG 具有体内肿瘤抑制功能，可与 p53 协同促进肿瘤发生，还表明 p53 具有 EMT 检查点功能，而这种功能的丧失可与 RKTG 的丧失相结合，从而驱动 EMT 和肿瘤进展。
