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 Genetjournal_title
PLoS geneticsauthors
Schmid T,Snoek LB,Fröhli E,van der Bent ML,Kammenga J,Hajnal Adoi
10.1371/journal.pgen.1005236subject
Has Abstractpub_date
2015-05-15 00:00:00pages
e1005236issue
5eissn
1553-7390issn
1553-7404pii
PGENETICS-D-15-00040journal_volume
11pub_type
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