Regulation of interferon and retinoic acid-induced cell death activation through thioredoxin reductase.
Interferons (IFNs) and retinoids are potent biological response modifiers. The IFN-beta and all-trans-retinoic acid combination, but not these single agents individually, induces death in several tumor cell lines. To elucidate the molecular basis for these actions, we have employed an antisense knockout approach to identify the gene products that mediate cell death and isolated several genes associated with retinoid-IFN-induced mortality (GRIMs). One of the GRIM cDNAs, GRIM-12, was identical to human thioredoxin reductase (TR). To define the functional relevance of TR to cell death and to define its mechanism of death-modulating functions, we generated mutants of TR and studied their influence on the IFN/RA-induced death regulatory functions of caspases. Wild-type TR activates cell death that was inhibited in the presence of caspase inhibitors or catalytically inactive caspases. A mutant TR, lacking the active site cysteines, inhibits the cell death induced by caspase 8. IFN/all-trans-retinoic acid-induced cytochrome c release from the mitochondrion was promoted in the presence of wild type and was inhibited in the presence of mutant TR. We find that TR modulates the activity of caspase 8 to promote death. This effect is in part caused by the stimulation of death receptor gene expression. These studies identify a new mechanism of cell death regulation by the IFN/all-trans-retinoic acid combination involving redox enzymes.
Ma
X
X
Greenebaum Cancer Center, Department of Microbiology and Immunology, Molecular and Cellular Biology Program, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Karra
S
S
Guo
W
W
Lindner
D J
DJ
Hu
J
J
Angell
J E
JE
Hofmann
E R
ER
Reddy
S P
SP
Kalvakolanu
D V
DV
D000818:Animals; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics*; D002460:Cell Line; D002645:Chickens; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D029721:Drosophila Proteins; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D008928:Mitochondria / Q000201:enzymology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D011817:Rabbits; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D029721:Drosophila Proteins; D009479:Neuropeptides; D018124:Receptors, Tumor Necrosis Factor; C108881:grim protein, Drosophila; D014212:Tretinoin; D007372:Interferons; D013880:Thioredoxin-Disulfide Reductase; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases