| First Author | Lee SH | Year | 2010 |
| Journal | Nat Med | Volume | 16 |
| Issue | 6 | Pages | 665-70 |
| PubMed ID | 20473309 | Mgi Jnum | J:161529 |
| Mgi Id | MGI:4459580 | Doi | 10.1038/nm.2143 |
| Citation | Lee SH, et al. (2010) ERK activation drives intestinal tumorigenesis in Apc(min/+) mice. Nat Med 16(6):665-70 |
| abstractText | Toll-like receptor (TLR) signaling is essential for intestinal tumorigenesis in Apc(min/+) mice, but the mechanisms by which Apc enhances tumor growth are unknown. Here we show that microflora-MyD88-ERK signaling in intestinal epithelial cells (IECs) promotes tumorigenesis by increasing the stability of the c-Myc oncoprotein. Activation of ERK (extracellular signal-related kinase) phosphorylates c-Myc, preventing its ubiquitination and subsequent proteasomal degradation. Accordingly, Apc(min/+)/Myd88(-/-) mice have lower phospho-ERK (p-ERK) levels and fewer and smaller IEC tumors than Apc(min/+) mice. MyD88 (myeloid differentiation primary response gene 88)-independent activation of ERK by epidermal growth factor (EGF) increased p-ERK and c-Myc and restored the multiple intestinal neoplasia (Min) phenotype in Apc(min/+)/Myd88(-/-) mice. Administration of an ERK inhibitor suppressed intestinal tumorigenesis in EGF-treated Apc(min/+)/Myd88(-/-) and Apc(min/+) mice and increased their survival. Our data reveal a new facet of oncogene-environment interaction, in which microflora-induced TLR activation regulates oncogene expression and related IEC tumor growth in a susceptible host. |
