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- 积分
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- 威望
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Functional Cooperation of RKTG with p53 in Tumorigenesis and Epithelial–Mesenchymal Transition2 j! R: S6 X- }, A2 h6 a- A
Yuhui Jiang1, Xiaoduo Xie1, Zhigang Li1, Zheng Wang1, Yixuan Zhang1, Zhiqiang Ling2, Yi Pan1, Zhenzhen Wang1, and Yan Chen1
g1 O$ o- U$ c) j: h$ F+ Rhttp://cancerres.aacrjournals.or ... 2-b490-3897bcf6b37e8 ?! B# J) l0 x8 s& ^
Authors' Affiliations:1Key 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; and 2Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China
. P9 V/ v# i4 U" _Corresponding Author:
. c2 n1 R" O* \Yan Chen, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Rd., Shanghai 200031, China. Phone: 86-21-54920916; Fax: 86-21-54920291; E-mail: ychen3@sibs.ac.cn
! Q: I% c: V+ |) R9 S OAbstract
Z& ?" M0 x) J1 G7 q9 G8 ]7 ~- PRaf 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. Cancer Res; 71(8); 2959–68. ©2011 AACR.
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发表于 2011-4-15 18:14
发表于 2011-4-16 19:55
