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Title

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

AuthorsGuerrero Arroyo, María del Carmen ; Martín-Encabo, Susana; Fernández-Medarde, Alberto; Santos de Dios, Eugenio
Issue Date2004
PublisherNature Publishing Group
CitationOncogene 23: 4885-4893 (2004)
AbstractWe 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 C3GACat mutant, lacking catalytic domain, we showed here that overexpression of cotransfected C3G or C3GACat inhibited oncogenic Hras lys12-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.
Publisher version (URL)http://dx.doi.org/10.1038/sj.onc.1207622
URIhttp://hdl.handle.net/10261/59648
DOI10.1038/sj.onc.1207622
Identifiersdoi: 10.1038/sj.onc.1207622
issn: 0950-9232
e-issn: 1476-5594
Appears in Collections:(IBMCC) Artículos
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