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- Title
Modulation of p53 dependent gene expression and cell death through thioredoxin-thioredoxin reductase by the Interferon-Retinoid combination.
- Authors
Hu, Jiadi; Ma, Xinrong; Lindner, Daniel J; Karra, Sreenivasu; Hofmann, Edward R; Reddy, Sekhar PM; Kalvakolanu, Dhananjaya V
- Abstract
We have shown earlier that the IFN-β 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. Oncogene (2001) 20, 4235–4248.
- Subjects
GENE expression; CELL death; INTERFERONS; CYTOKINES
- Publication
Oncogene, 2001, Vol 20, Issue 31, p4235
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1204585