ERK activation drives intestinal tumorigenesis in Apcmin/+ mice

SH Lee, LL Hu, J Gonzalez-Navajas, GS Seo… - Nature medicine, 2010 - nature.com
SH Lee, LL Hu, J Gonzalez-Navajas, GS Seo, C Shen, J Brick, S Herdman, N Varki, M Corr…
Nature medicine, 2010nature.com
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 …
Abstract
Toll-like receptor (TLR) signaling is essential for intestinal tumorigenesis in Apcmin/+ 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, Apcmin/+/Myd88−/− mice have lower phospho-ERK (p-ERK) levels and fewer and smaller IEC tumors than Apcmin/+ 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 Apcmin/+/Myd88−/− mice. Administration of an ERK inhibitor suppressed intestinal tumorigenesis in EGF-treated Apcmin/+/Myd88−/− and Apcmin/+ 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.
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