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P53 orchestrates the PGC-1?-mediated antioxidant response upon mild redox and metabolic imbalance.

ABSTRACT: The transcriptional coactivator peroxisome proliferator-activated receptor-? coactivator-1 ? (PPARGC1A or PGC-1?) is a powerful controller of cell metabolism and assures the balance between the production and the scavenging of pro-oxidant molecules by coordinating mitochondrial biogenesis and the expression of antioxidants. However, even though a huge amount of data referring to the role of PGC-1? is available, the molecular mechanisms of its regulation at the transcriptional level are not completely understood. In the present report, we aim at characterizing whether the decrease of antioxidant glutathione (GSH) modulates PGC-1? expression and its downstream metabolic pathways.We found that upon GSH shortage, induced either by its chemical depletion or by metabolic stress (i.e., fasting), p53 binds to the PPARGC1A promoter of both human and mouse genes, and this event is positively related to increased PGC-1? expression. This effect was abrogated by inhibiting nitric oxide (NO) synthase or guanylate cyclase, implicating NO/cGMP signaling in such a process. We show that p53-mediated PGC-1? upregulation is directed to potentiate the antioxidant defense through nuclear factor (erythroid-derived 2)-like2 (NFE2L2)-mediated expression of manganese superoxide dismutase (SOD2) and ?-glutamylcysteine ligase without modulating mitochondrial biogenesis.We outlined a new NO-dependent signaling axis responsible for survival antioxidant response upon mild metabolic stress (fasting) and/or oxidative imbalance (GSH depletion). Such signaling axis could become the cornerstone for new pharmacological or dietary approaches for improving antioxidant response during ageing and human pathologies associated with oxidative stress.

SUBMITTER: Aquilano K

PROVIDER: S-EPMC3526895 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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p53 orchestrates the PGC-1α-mediated antioxidant response upon mild redox and metabolic imbalance.

Aquilano Katia K Baldelli Sara S Pagliei Beatrice B Cannata Stefano M SM Rotilio Giuseppe G Ciriolo Maria R MR

Antioxidants & redox signaling 20120920 4

<h4>Aims</h4>The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1 α (PPARGC1A or PGC-1α) is a powerful controller of cell metabolism and assures the balance between the production and the scavenging of pro-oxidant molecules by coordinating mitochondrial biogenesis and the expression of antioxidants. However, even though a huge amount of data referring to the role of PGC-1α is available, the molecular mechanisms of its regulation at the transcriptional level ...[more]

PMID: 22861165

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Project description:A metabolomics study demonstrated a decrease in glutathione and an increase in cysteine (Cys) levels in human prostate cancer (PCa) tissues as Gleason scores increased, indicating redox imbalance with PCa progression. These results were extended in the present study by analyzing the redox state of the protein thioredoxin 1 (Trx1) and sulfinylation (SO3) of peroxiredoxins (Prxs) (PrxSO3) in PCa tissues and cell lines. Lysates of paired human PCa tissues with varying degrees of aggressiveness and adjacent benign (BN) tissues were used for analysis. Redox Western blot analysis of Trx1 demonstrated low levels of reduced and high levels of oxidized Trx1 (functional and nonfunctional, respectively) in high-grade PCa (Gleason scores 4+4 to 4+5) in comparison to intermediate-grade PCa (Gleason scores 3+3 to 3+4) or BN tissues. PrxSO3 were increased in high-grade PCa. Oxidized Trx1 and PrxSO3 are indicators of oxidative stress. To study whether redox imbalance may potentially affect enzyme activities of antioxidant proteins (APs), we determined the levels of selected APs in PCa tissues by Western blot analysis and found that mitochondrial manganese superoxide dismutase (MnSOD), Prx3, and Trx1 were increased in high-grade PCa tissues compared with BN tissues. Enzyme activities of MnSOD in high-grade PCa tissues were significantly increased but at a lower magnitude compared with the levels of MnSOD protein (0.5-fold vs 2-fold increase). Trx1 activity was not changed in high-grade PCa tissues despite a large increase in Trx1 protein expression. Further studies demonstrated a significant increase in posttranslational modifications of tyrosine and lysine residues in MnSOD protein and oxidation of Cys at the active site (Cys32 and Cys35) and the regulatory site (Cys62 and Cys69) of Trx1 in high-grade PCa compared to BN tissues. These discordant changes between protein levels and enzyme activities are consistent with protein inactivation by redox imbalance and/or posttranslational modifications. In contrast, the protein level and activity of extracellular superoxide dismutase were significantly decreased in high-grade PCa compared with adjacent BN tissues. Results from cell lines mirror those from PCa tissues. Knowledge of redox-state profiles in specific cancers may help to predict the behavior and response of each cancer to chemotherapeutic drugs and radiation.

Dataset Information

P53 orchestrates the PGC-1?-mediated antioxidant response upon mild redox and metabolic imbalance.

Publications

p53 orchestrates the PGC-1α-mediated antioxidant response upon mild redox and metabolic imbalance.

Similar Datasets

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