Format

Send to

Choose Destination
PLoS Genet. 2015 May 15;11(5):e1005236. doi: 10.1371/journal.pgen.1005236. eCollection 2015 May.

Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA.

Author information

1
University of Zurich, Institute of Molecular Life Sciences, Zurich, Switzerland; PhD Program in Molecular Life Sciences, University and ETH Zurich, Zurich, Switzerland.
2
Laboratory of Nematology, Wageningen University, Wageningen, The Netherlands.
3
University of Zurich, Institute of Molecular Life Sciences, Zurich, Switzerland.

Abstract

Human cancer is caused by the interplay of mutations in oncogenes and tumor suppressor genes and inherited variations in cancer susceptibility genes. While many of the tumor initiating mutations are well characterized, the effect of genetic background variation on disease onset and progression is less understood. We have used C. elegans genetics to identify genetic modifiers of the oncogenic RAS/MAPK signaling pathway. Quantitative trait locus analysis of two highly diverged C. elegans isolates combined with allele swapping experiments identified the polymorphic monoamine oxidase A (MAOA) gene amx-2 as a negative regulator of RAS/MAPK signaling. We further show that the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is a product of MAOA catalysis, systemically inhibits RAS/MAPK signaling in different organs of C. elegans. Thus, MAOA activity sets a global threshold for MAPK activation by controlling 5-HIAA levels. To our knowledge, 5-HIAA is the first endogenous small molecule that acts as a systemic inhibitor of RAS/MAPK signaling.

PMID:
25978500
PMCID:
PMC4433219
DOI:
10.1371/journal.pgen.1005236
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center