Proc Natl Acad Sci U S A 2010,
PMID: 20566882
Khutornenko, Anastasia A; Roudko, Vladimir V; Chernyak, Boris V; Vartapetian, Andrey B; Chumakov, Peter M; Evstafieva, Alexandra G
While many functions of the p53 tumor suppressor affect mitochondrial processes, the role of altered mitochondrial physiology in a modulation of p53 response remains unclear. As mitochondrial respiration is affected in many pathologic conditions such as hypoxia and intoxications, the impaired electron transport chain could emit additional p53-inducing signals and thereby contribute to tissue damage. Here we show that a shutdown of mitochondrial respiration per se does not trigger p53 response, because inhibitors acting in the proximal and distal segments of the respiratory chain do not activate p53. However, strong p53 response is induced specifically after an inhibition of the mitochondrial cytochrome bc1 (the electron transport chain complex III). The p53 response is triggered by the deficiency in pyrimidines that is developed due to a suppression of the functionally coupled mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH). In epithelial carcinoma cells the activation of p53 in response to mitochondrial electron transport chain complex III inhibitors does not require phosphorylation of p53 at Serine 15 or up-regulation of p14(ARF). Instead, our data suggest a contribution of NQO1 and NQO2 in stabilization of p53 in the nuclei. The results establish the deficiency in pyrimidine biosynthesis as the cause of p53 response in the cells with impaired mitochondrial respiration.
Document information provided by NCBI PubMed
Text Mining Data
p14(ARF) → p53: "
In epithelial carcinoma cells the activation of
p53 in response to mitochondrial electron transport chain complex III inhibitors does not
require phosphorylation of p53 at Serine 15 or up-regulation of
p14(ARF)
"
p53 → p14(ARF): "
In epithelial carcinoma cells the activation of p53 in response to mitochondrial electron transport chain complex III inhibitors does not require phosphorylation of p53 at Serine 15 or up-regulation of p14(ARF)
"
Manually curated Databases
No curated data.