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

Tobias Schmid,L Basten Snoek,Erika Fröhli,Alex Hajnal,Jan Kammenga,M Leontien Van Der Bent,Stuart K Kim

doi:10.1371/journal.pgen.1005236

Tobias Schmid, L Basten Snoek + Show 5 more

Open Access

https://doi.org/10.1371/journal.pgen.1005236

Copy DOI

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.

Highlights

Human cancer is a complex polygenic disease caused by somatic mutations in oncogenes and tumor suppressor genes together with inherited polymorphisms in cancer susceptibility genes
We further show that the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is a product of monoamine oxidase A (MAOA) catalysis, systemically inhibits RAS/MAPK signaling in different organs of C. elegans
We have used the roundworm Caenorhabditis elegans (C. elegans) as a model to investigate how the genetic composition of the animal affects the outcome of oncogenic RAS mutations that activate the MAPK pathway

Summary

Introduction

Human cancer is a complex polygenic disease caused by somatic mutations in oncogenes and tumor suppressor genes together with inherited polymorphisms in cancer susceptibility genes. Many of the oncogenes and tumor suppressor genes that are mutated in different cancer types have been investigated in detail. The components of the RAS/MAPK signaling pathway are mutated in a large fraction of human tumors. Thanks to the strong conservation of this pathway in metazoans, genetic studies in model organisms, such as the nematode Caenorhabditis elegans, have provided important insights into various factors modulating RAS/MAPK signaling [4]. C. elegans has become a platform species for quantitative genetic analyses of various phenotypes and pathways in order to identify and characterize polymorphic genes [5,6]

Methods

Results

Discussion

Conclusion