title: Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA.
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.
authors.affiliation: University of Zurich, Institute of Molecular Life Sciences, Zurich, Switzerland; PhD Program in Molecular Life Sciences, University and ETH Zurich, Zurich, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmid
authors.affiliation: Laboratory of Nematology, Wageningen University, Wageningen, The Netherlands.
authors.forename: L Basten
authors.initials: LB
authors.lastname: Snoek
authors.affiliation: University of Zurich, Institute of Molecular Life Sciences, Zurich, Switzerland.
authors.forename: Erika
authors.initials: E
authors.lastname: Fröhli
authors.affiliation: Laboratory of Nematology, Wageningen University, Wageningen, The Netherlands.
authors.forename: M Leontien
authors.initials: ML
authors.lastname: van der Bent
authors.affiliation: Laboratory of Nematology, Wageningen University, Wageningen, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Kammenga
authors.affiliation: University of Zurich, Institute of Molecular Life Sciences, Zurich, Switzerland.
authors.forename: Alex
authors.initials: A
authors.lastname: Hajnal
mesh_terms: D000483:Alleles; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping; D005786:Gene Expression Regulation; D060005:Genotyping Techniques; D006897:Hydroxyindoleacetic Acid / Q000737:chemistry*; D020935:MAP Kinase Signaling System; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci; D012701:Serotonin / Q000737:chemistry*; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins; D047428:Protein Kinase Inhibitors; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D008995:Monoamine Oxidase; D016283:Proto-Oncogene Proteins p21(ras)