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.
Matos
Paulo
P
Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal.
Jordan
Peter
P
Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal. Electronic address: peter.jordan@insa.min-saude.pt.
D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D011232:Chemical Precipitation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016384:Consensus Sequence / Q000235:genetics; D044842:Cullin Proteins / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism*; D014158:Transcription, Genetic; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D052003:NF-kappa B p52 Subunit; C107953:RAC1 protein, human; C498143:RELA protein, human; C497593:RELB protein, human; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D019938:Cyclin D1; D051841:Transcription Factor RelB; D051550:I-kappa B Kinase; D020830:rac1 GTP-Binding Protein