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

T. Schmid, L.B. Snoek, E. Fröhli, M.L. van der Bent, J.E. Kammenga, A. Hajnal

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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.
Original languageEnglish
Article numbere1005236
Number of pages16
JournalPlos Genetics
Volume11
Issue number5
DOIs
Publication statusPublished - 2015

Fingerprint

5-hydroxyindoleacetic acid
amine oxidase (flavin-containing)
Hydroxyindoleacetic Acid
Monoamine Oxidase
serotonin
Serotonin
metabolite
metabolites
neoplasms
acid
tumor
mutation
gene
cancer
Mutation
tumor suppressor genes
modifiers (genes)
Quantitative Trait Loci
Neoplasm Genes
oncogenes

Keywords

  • caenorhabditis-elegans
  • c-elegans
  • natural variation
  • vulvar induction
  • complex disease
  • receptor
  • protein
  • gene
  • kinase
  • activation

Cite this

Schmid, T., Snoek, L. B., Fröhli, E., van der Bent, M. L., Kammenga, J. E., & Hajnal, A. (2015). Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA. Plos Genetics, 11(5), [e1005236]. https://doi.org/10.1371/journal.pgen.1005236
Schmid, T. ; Snoek, L.B. ; Fröhli, E. ; van der Bent, M.L. ; Kammenga, J.E. ; Hajnal, A. / Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA. In: Plos Genetics. 2015 ; Vol. 11, No. 5.
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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.",
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Schmid, T, Snoek, LB, Fröhli, E, van der Bent, ML, Kammenga, JE & Hajnal, A 2015, 'Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA' Plos Genetics, vol. 11, no. 5, e1005236. https://doi.org/10.1371/journal.pgen.1005236

Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA. / Schmid, T.; Snoek, L.B.; Fröhli, E.; van der Bent, M.L.; Kammenga, J.E.; Hajnal, A.

In: Plos Genetics, Vol. 11, No. 5, e1005236, 2015.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Schmid, T.

AU - Snoek, L.B.

AU - Fröhli, E.

AU - van der Bent, M.L.

AU - Kammenga, J.E.

AU - Hajnal, A.

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AB - 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.

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