Rac1, but not Rac1B, stimulates RelB-mediated gene transcription in colorectal cancer cells.

Increased NF-kappaB-mediated transcription has been extensively linked to tumorigenesis and can be stimulated by deregulated Rac1 signaling. For example, the overexpression of Rac1b, a highly activated splicing variant of Rac1 with increased expression in colorectal tumors, stimulates NF-kappaB-mediated G1/S progression and cell survival, and was shown to promote cell transformation ...
and epithelial-mesenchymal transition. Here we show evidence of further complexity between Rac1b and Rac1 signaling toward NF-kappaB in colorectal cells. Consistent with data from other cell types we demonstrate that both Rac1 and Rac1b stimulate transcriptional activation from reporter genes driven by NF-kappaB motifs or the cyclin D1 promoter in an IkappaBalpha- and reactive oxygen species-dependent manner. However, we found that in colorectal cells Rac1, but not Rac1b, induces nuclear translocation of RelB and p52, activates transcription from a RelB-specific reporter, and can be isolated in a complex with endogenous RelB and its inhibitor NF-kappaB2/p100. In addition, Rac1 colocalizes at the plasma membrane with RelB, p100, and cullin-1, a core subunit of the E3 ubiquitin ligase that marks p100 for proteolytic processing to p52. Interestingly, this Rac1-specific pathway is not mediated via the production of reactive oxygen species. These data provide evidence that both Rac1 and Rac1b activate the canonical RelA-IkappaBalpha pathway, whereas Rac1 further stimulates NF-kappaB by inducing the RelB-NF-kappaB2/p100 pathway. The RelB pathway was reported to down-regulate canonical NF-kappaB activation during the inflammatory response, suggesting that increased levels of Rac1b in colorectal tumors may promote tumorigenesis by stimulating canonical NF-kappaB signaling while circumventing a negative feedback from the RelB pathway.
Mesh Terms:
Cell Cycle Proteins, Cell Line, Tumor, Cell Membrane, Chemical Precipitation, Colorectal Neoplasms, Consensus Sequence, Cullin Proteins, Cyclin D1, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, I-kappa B Kinase, NF-kappa B p52 Subunit, Promoter Regions, Genetic, Protein Transport, Reactive Oxygen Species, Transcription Factor RelA, Transcription Factor RelB, Transcription, Genetic, rac1 GTP-Binding Protein
J. Biol. Chem.
Date: May. 12, 2006
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