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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Chromosome Mapping
  • Gene Expression Regulation*
  • Genotyping Techniques
  • Hydroxyindoleacetic Acid / chemistry*
  • MAP Kinase Signaling System*
  • Monoamine Oxidase / genetics
  • Monoamine Oxidase / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Quantitative Trait Loci
  • Serotonin / chemistry*
  • Signal Transduction

Substances

  • Caenorhabditis elegans Proteins
  • Protein Kinase Inhibitors
  • Serotonin
  • Hydroxyindoleacetic Acid
  • Monoamine Oxidase
  • Proto-Oncogene Proteins p21(ras)

Grant support

This work was supported by the Kanton of Zurich, the PANACEA EU FP project contract nr. 222936 and a grant from the Swiss National Science Foundation to AH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.