ERK activation drives intestinal tumorigenesis in Apc(min/+) mice.
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.
Lee
Sung Hee
SH
Department of Medicine, University of California, San Diego, La Jolla, California, USA.
Hu
Li-Li
LL
Gonzalez-Navajas
Jose
J
Seo
Geom Seog
GS
Shen
Carol
C
Brick
Jonathan
J
Herdman
Scott
S
Varki
Nissi
N
Corr
Maripat
M
Lee
Jongdae
J
Raz
Eyal
E
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D017491:Genes, APC / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000502:physiology; D007414:Intestinal Neoplasms / Q000235:genetics*; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
C489428:Myc protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016271:Proto-Oncogene Proteins c-myc; D048049:Extracellular Signal-Regulated MAP Kinases
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