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.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

Schmid T,Snoek LB,Fröhli E,van der Bent ML,Kammenga J,Hajnal A

doi

10.1371/journal.pgen.1005236

subject

Has Abstract

pub_date

2015-05-15 00:00:00

pages

e1005236

issue

5

eissn

1553-7390

issn

1553-7404

pii

PGENETICS-D-15-00040

journal_volume

11

pub_type

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