| RRC ID |
45966
|
| Author |
Ferguson AA, Roy S, Kormanik KN, Kim Y, Dumas KJ, Ritov VB, Matern D, Hu PJ, Fisher AL.
|
| Title |
TATN-1 mutations reveal a novel role for tyrosine as a metabolic signal that influences developmental decisions and longevity in Caenorhabditis elegans.
|
| Journal |
PLoS Genet
|
| Abstract |
Recent work has identified changes in the metabolism of the aromatic amino acid tyrosine as a risk factor for diabetes and a contributor to the development of liver cancer. While these findings could suggest a role for tyrosine as a direct regulator of the behavior of cells and tissues, evidence for this model is currently lacking. Through the use of RNAi and genetic mutants, we identify tatn-1, which is the worm ortholog of tyrosine aminotransferase and catalyzes the first step of the conserved tyrosine degradation pathway, as a novel regulator of the dauer decision and modulator of the daf-2 insulin/IGF-1-like (IGFR) signaling pathway in Caenorhabditis elegans. Mutations affecting tatn-1 elevate tyrosine levels in the animal, and enhance the effects of mutations in genes that lie within the daf-2/insulin signaling pathway or are otherwise upstream of daf-16/FOXO on both dauer formation and worm longevity. These effects are mediated by elevated tyrosine levels as supplemental dietary tyrosine mimics the phenotypes produced by a tatn-1 mutation, and the effects still occur when the enzymes needed to convert tyrosine into catecholamine neurotransmitters are missing. The effects on dauer formation and lifespan require the aak-2/AMPK gene, and tatn-1 mutations increase phospho-AAK-2 levels. In contrast, the daf-16/FOXO transcription factor is only partially required for the effects on dauer formation and not required for increased longevity. We also find that the controlled metabolism of tyrosine by tatn-1 may function normally in dauer formation because the expression of the TATN-1 protein is regulated both by daf-2/IGFR signaling and also by the same dietary and environmental cues which influence dauer formation. Our findings point to a novel role for tyrosine as a developmental regulator and modulator of longevity, and support a model where elevated tyrosine levels play a causal role in the development of diabetes and cancer in people.
|
| Volume |
9(12)
|
| Pages |
e1004020
|
| Published |
2013-1-1
|
| DOI |
10.1371/journal.pgen.1004020
|
| PII |
PGENETICS-D-13-00168
|
| PMID |
24385923
|
| PMC |
PMC3868569
|
| MeSH |
Animals
Animals, Genetically Modified
Caenorhabditis elegans / genetics
Caenorhabditis elegans / growth & development*
Caenorhabditis elegans Proteins / genetics*
Forkhead Transcription Factors
Gene Expression Regulation, Developmental
Green Fluorescent Proteins
Humans
Insulin / metabolism
Insulin-Like Growth Factor I / metabolism
Larva / genetics
Larva / growth & development
Larva / metabolism
Longevity / genetics*
Metabolic Networks and Pathways / genetics*
Mutation
RNA Interference
Receptor, Insulin / metabolism
Transcription Factors / genetics
Tyrosine / genetics*
Tyrosine / metabolism
Tyrosine Transaminase / genetics*
|
| IF |
5.175
|
| Times Cited |
28
|
|
WOS Category
|
GENETICS & HEREDITY
|
| Resource |
| C.elegans |
tm3188 |
