Redox regulation of human P53 tumor suppressor gene activity: Identification of redox genes that play role in human P53 reporter gene activity

Abstract

The occurence of p53 gene mutations in many human tumors shows that p53 protein plays an important role in preventing cancers. One of the most important function of p53 protein is its ability to stimulate transcription of other genes that inhibit cell cycle progression and DNA repair mechanisms or apoptosis pathways. p53 gene activity is controlled by a series of mechanisms among which redox regulation has taken little attention. Because of its importance as a tumor suppressor, its role as a cell cycle control protein and transcription factor, we decided to focus on p53 transcriptional activity. Human p53 can be studied in yeast where genetic tools can be used to identify proteins that affect its ability to stimulate transcription of reporter genes. Several studies have shown that the p53 protein is prone to oxidative inactivation. Although yeast does not contain a p53 gene, the similarity of cell cycle control mechanisms and oxidative stress response pathways prompted us to ask whether human p53 was active in yeast cells lacking individual antioxidant genes. In this study, using yeast deletion mutants, p53 reporter gene activity was assayed in different antioxidant mutants that were identified by REDOX-Cys-Search bioinformatic tool by previous studies. Seven antioxidant genes were found to be important in regulating p53 activity. These genes played role in phosphatidylinositol pathway, protein dephosphorylation, cellular iron metabolism, DNA mismatch repair, and three other unknown biochemical pathways.Identification of these new proteins that regulate p53 activity may have broad implications in understanding the complex behaviour of p53 and tumor formation in humans.