Expression of tumor-related Rac1b antagonizes B-Raf-induced senescence in colorectal cells

Cancer Letters
Andreia HenriquesPeter Jordan

Abstract

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 around 80% of colorectal tumors carrying a mutation in BRAF also overexpress splice variant Rac1b. We used normal NCM460 colonocytes as a model to express oncogenic B-Raf-V600E in the presence or absence of co-transfected Rac1b and then analyzed the effect on expression of senescence markers. When oncogenic B-Raf-V600E was expressed we observed the induction of the senescence-associated β-galactosidase and of the cell-cycle inhibitors p14, p15 and p21 whereas proliferation marker Ki67 was suppressed. Upon co-expression of splice variant Rac1b, but not of Rac1, the B-Raf-induced senescence phenotype was reverted and expression of the cell-cycle inhibitors downregulated in a reactive oxygen-species dependent manner. We thus provide evidence that co-expression of splice variant Rac1b counteracts B-Raf-induced senescence, indicating the sele...Continue Reading

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Citations

May 6, 2016·Cellular and Molecular Life Sciences : CMLS·Joana F S PereiraPeter Jordan
Apr 9, 2017·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Hendrik UngefrorenHendrik Lehnert
Aug 16, 2018·International Journal of Cancer. Journal International Du Cancer·Huizi WuJochen Utikal
Mar 18, 2020·Cancers·Larissa Kotelevets, Eric Chastre
Aug 31, 2021·Frontiers in Cell and Developmental Biology·Jing YangXing Zhang

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