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-beta 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.
Hu
J
J
Greenebaum Cancer Center, Department of Microbiology & Immunology, Molecular and Cellular Biology Program, University of Maryland School of Medicine, Baltimore, Maryland, MD 21201, USA.
Ma
X
X
Lindner
D J
DJ
Karra
S
S
Hofmann
E R
ER
Reddy
S P
SP
Kalvakolanu
D V
DV
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D001426:Bacterial Proteins; D001483:Base Sequence; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000008:administration & dosage*; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
D001426:Bacterial Proteins; D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; C096391:thioredoxin-thioredoxin reductase hybrid protein, Mycobacterium leprae; D013879:Thioredoxins; D014212:Tretinoin; D016899:Interferon-beta; D013880:Thioredoxin-Disulfide Reductase