Modulation of p53 dependent gene expression and cell death through thioredoxin-thioredoxin reductase by the interferon-retinoid combination

We have shown earlier that the IFN-P and all-trans retinoic acid (RA) combination, but not the single agents, induces death in several tumor cell lines. Employing a genetic technique we have identified several Genes associated with Retinoid-IFN induced Mortality (GRIM), One of the GRIMs was human thioredoxin reductase (TR), a redox enzyme. Since the overexpressed TR augments IFN/RA stimulated cell death, we explored the mechanisms of TR-mediated death, Here we show that TR augments cell death by upregulating the transcriptional activity of p53 tumor suppressor. This process does not involve a physical increase in levels of p53, Using redox inactive mutants of TR and its substrate, thioredoxin (Trx), we demonstrate that IFN/ RA-induced regulation of p53 dependent gene expression requires TR and Trx, In contrast-over-expression of wildtype TR or Trx augment the p53 dependent gene expression in response to IFN/RA treatment. Consistent with these results an increased DNA binding activity of p53 was noted in the presence of TR, These studies identify a novel mechanism of p53 mediated cell death regulation involving redox enzymes.