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Gankyrin plays an essential role in Ras-induced tumorigenesis through regulation of the RhoA/ROCK pathway in mammalian cells
Jiang-Hong Man, … , Hui-Yan Li, Xue-Min Zhang
Jiang-Hong Man, … , Hui-Yan Li, Xue-Min Zhang
Published July 12, 2010
Citation Information: J Clin Invest. 2010;120(8):2829-2841. https://doi.org/10.1172/JCI42542.
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Research Article Oncology

Gankyrin plays an essential role in Ras-induced tumorigenesis through regulation of the RhoA/ROCK pathway in mammalian cells

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Abstract

Activating mutations in Ras proteins are present in about 30% of human cancers. Despite tremendous progress in the study of Ras oncogenes, many aspects of the molecular mechanisms underlying Ras-induced tumorigenesis remain unknown. Through proteomics analysis, we previously found that the protein Gankyrin, a known oncoprotein in hepatocellular carcinoma, was upregulated during Ras-mediated transformation, although the functional consequences of this were not clear. Here we present evidence that Gankyrin plays an essential role in Ras-initiated tumorigenesis in mouse and human cells. We found that the increased Gankyrin present following Ras activation increased the interaction between the RhoA GTPase and its GDP dissociation inhibitor RhoGDI, which resulted in inhibition of the RhoA effector kinase Rho-associated coiled coil–containing protein kinase (ROCK). Importantly, Gankyrin-mediated ROCK inhibition led to prolonged Akt activation, a critical step in activated Ras–induced transformation and tumorigenesis. In addition, we found that Gankyrin is highly expressed in human lung cancers that have Ras mutations and that increased Gankyrin expression is required for the constitutive activation of Akt and tumorigenesis in these lung cancers. Our findings suggest that Gankyrin is a key regulator of Ras-mediated activation of Akt through inhibition of the downstream RhoA/ROCK pathway and thus plays an essential role in Ras-induced tumorigenesis.

Authors

Jiang-Hong Man, Bing Liang, Yue-Xi Gu, Tao Zhou, Ai-Ling Li, Tao Li, Bao-Feng Jin, Bing Bai, Hai-Ying Zhang, Wei-Na Zhang, Wei-Hua Li, Wei-Li Gong, Hui-Yan Li, Xue-Min Zhang

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Figure 3

Gankyrin interacts with RhoGDI1 and increases the association of RhoGDI1 and RhoA.

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Gankyrin interacts with RhoGDI1 and increases the association of RhoGDI1...
(A) Immunoassay of HEK293 cells cotransfected with vectors expressing Flag-Gankyrin and Myc-RhoGDI1. Lysates were immunoprecipitated with anti-Flag and then analyzed by immunoblot with anti-Myc and anti-Flag antibodies. WCLs, whole cell lysates. (B) Immunoblot analysis of bound proteins in lysates of HEK293 cells expressing Myc-RhoGDI1, incubated with Sepharose beads coupled to GST alone or a fusion protein of GST and Gankyrin (GST-Gankyrin). CBB, Coomassie brilliant blue staining. (C) Immunoblot analysis of the interaction among endogenous Gankyrin, RhoA, and RhoGDI1 in lysates of HEK293 cells after immunoprecipitation with rabbit IgG or anti-RhoGDI1 (left) and whole cell lysates (right). (D) Immunoassay of HEK293 cells cotransfected with vectors expressing Flag-Gankyrin, Myc-RhoA, and Myc-RhoGDI1. Lysates were immunoprecipitated with anti-Flag and analyzed by immunoblot with anti-Myc and anti-Flag antibodies. (E) Immunoblot analysis of the interaction among endogenous Gankyrin, RhoA, and RhoGDI1 in lysates of HEK293 cells after immunoprecipitation with rabbit IgG or anti-Gankyrin (left) and whole cell lysates (right). (F) Immunoassay of HEK293 cells transfected with increasing amounts of Flag-Gankyrin. RhoGDI1 in lysates was immunoprecipitated with anti-RhoGDI1, followed by immunoblot analysis of immunoprecipitates (left) and whole cell lysates (right).
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