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C3G-mediated suppression of oncogene-induced focus formation in fibroblasts involves inhibition of ERK activation, cyclin A expression and alterations of anchorage-independent growth

Oncogene volume 23, pages 4885–4893 (2004)Cite this article

Abstract

We showed previously that exogenous overexpression of C3G, a guanine nucleotide releasing factor (GEF) for Rap1 and R-Ras proteins, blocks the focus-forming activity of cotransfected, activated, sis, ras and v-raf oncogenes in NIH 3T3 cells. In this report, we show that C3G also interferes with dbl and R-Ras focus-forming activity and demonstrate that the transformation suppressor ability of C3G maps to its Crk-binding region (SH3-b domain). Using full-length C3G and C3GΔCat mutant, lacking catalytic domain, we showed here that overexpression of cotransfected C3G or C3GΔCat inhibited oncogenic Hraslys12-mediated phosphorylation of ERK, without altering Ras and Raf-1 kinase activation. We also showed that, overexpressed C3G and C3GΔCat inhibited the viability of oncogenic Ras-induced colonies in soft agar, indicating that C3G interferes with the anchorage-independent growth of Ras-transformed cells in a Rap1-independent manner. Consistent with both observations, overexpression of exogenous C3G and C3GΔCat also caused downregulation of Ras-induced cyclin A expression. Altogether, our results indicate that C3G interferes with at least two separate aspects of oncogenic transformation – cell cycle progression and loss of contact inhibition – and that these inhibitory effects probably account for its transformation suppressor activity.

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Acknowledgements

This work was supported by grants SAF00-0069 from MCYT and PI021570 from FIS, Spain. CG was supported by the Ramón y Cajal Program from MCYT.

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  1. Centro de Investigación del Cáncer, IBMCC, Universidad de Salamanca-CSIC, Salamanca, 37007, Spain

    Carmen Guerrero, Susana Martín-Encabo, Alberto Fernández-Medarde & Eugenio Santos

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  1. Carmen Guerrero
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  2. Susana Martín-Encabo
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Correspondence to Eugenio Santos.

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Guerrero, C., Martín-Encabo, S., Fernández-Medarde, A. et al. C3G-mediated suppression of oncogene-induced focus formation in fibroblasts involves inhibition of ERK activation, cyclin A expression and alterations of anchorage-independent growth. Oncogene 23, 4885–4893 (2004). https://doi.org/10.1038/sj.onc.1207622

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