Journal
CELL STEM CELL
Volume 12, Issue 6, Pages 761-773Publisher
CELL PRESS
DOI: 10.1016/j.stem.2013.04.006
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Funding
- Cancer Research UK
- AICR grant
- European Union [278568]
- Cancer Research UK [15565, 12481] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G1000078/1] Funding Source: researchfish
- Worldwide Cancer Research [10-0643] Funding Source: researchfish
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The Adenomatous Polyposis Coli (APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic development. Here, we show that RAC1 is a critical mediator of tumorigenesis after APC loss. We find that RAC1 is required for expansion of the LGR5 intestinal stem cell (ISC) signature, progenitor hyperproliferation, and transformation. Mechanistically, RAC1-driven ROS and NF-kappa B signaling mediate these processes. Together, these data highlight that ROS production and NF-kappa B activation triggered by RAC1 are critical events in CRC initiation.
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