Rac1b expression reverts B-Raf-V600E-induced senescence in colorectal cells

Henriques, Andreia; Barros, Patrícia; Matos, Paulo; Jordan, Peter

http://hdl.handle.net/10400.18/2487

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Abstract(s)

Mutations in the BRAF oncogene have been identified as a tumor-initiating genetic event in mainly melanoma, thyroid and colon cancer, resulting in an initial proliferative stimulus that is followed by a growth arrest period known as oncogene-induced senescence (OIS). It remains unknown what triggers subsequent escape from OIS to allow further tumor progression. A previous analysis revealed that overexpression of splice variant Rac1b occurs in around 80% of colorectal tumors carrying a mutation in BRAF. Using both BRaf-V600E-directed RNAi and overexpression we demonstrate that this mutation does not directly lead to Rac1b overexpression, indicating the latter as an independent event during tumor progression. Nonetheless, we observed that expression of oncogenic BRaf-V600E in non-transformed colonocytes (NCM460 cell line) increased both the transcript and protein levels of p14 ARF, p15 INK4b and p21 CIP1 and led to increased expression of β-galactosidase, all indicators of OIS induction. Importantly, the co-expression of Rac1b with B-Raf-V600E reverted the OIS phenotype, reducing the protein expression levels of the cell-cycle inhibitors and β-galactosidase activity to those of control cells. These data identify increased Rac1b expression as one potential mechanism by which colorectal tumor cells can escape from B-Raf-induced OIS.

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Abstract publicado em: 1st ASPIC International congress: proceedings book, p. 40. Disponível em: http://1stcongress.aspic.pt/sites/default/files/proceedins_book_web.2.pdf