Journal
CELL CYCLE
Volume 11, Issue 24, Pages 4589-4596Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.22853
Keywords
NADPH oxidase; p53; reactive oxygen species; apoptosis; p53 family members
Categories
Funding
- Alleanza Contro il Cancro [ACC12]
- Italian Human Proteome Net [RBRN07BMCT]
- Telethon Grant [GGPO9133]
- AIRC 5xmille [9979]
- AIRC [IG1195]
- Min. Salute [Ricercaoncologica 26/07]
- IDI-IRCCS [RF07 c.57, RF08 c.15]
- [MIUR/PRIN 2008MRLSNZ_004]
- MRC [MC_U132670600] Funding Source: UKRI
- Medical Research Council [MC_U132670600] Funding Source: researchfish
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Analysis of microarrays performed in p53-, TAp63 alpha- and Delta Np63 alpha-inducible SaOs-2 cell lines allowed the identification of NCF2 mRNA upregulation in response to p53 induction. NCF2 gene encodes for p67phox, the cytosolic subunit of the NADPH oxidase enzyme complex. The recruitment of p67phox to the cell membrane causes the activation of the NADPH oxidase complex followed by the generation of NADP+ and superoxide from molecular oxygen. The presence of three putative p53 binding sites on the NCF2 promoter was predicted, and the subsequent luciferase and chromatin immunoprecipitation assays showed the activation of NCF2 promoter by p53 and its direct binding in vivo to at least one of the sites, thus confirming the hypothesis. NCF2 upregulation was also confirmed by real-time PCR in several cell lines after p53 activation. NCF2 knockdown by siRNA results in a significant reduction of ROS production and stimulates cell death, suggesting a protective function of Nox2-generated ROS in cells against apoptosis. These results provide insight into the redox-sensitive signaling mechanism that mediates cell survival involving p53 and its novel target NCF2/p67phox.
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