The thioredoxin/thioredoxin reductase redox system and control of cell growth.
Thioredoxin is a redox protein that is important for a variety of intracellular functions, possibly including regulation of transcription factor activity. We have shown that human thioredoxin has the same predicted amino acid sequence as adult T-cell-derived leukemic cell growth factor. Recombinant human thioredoxin stimulates the proliferation of Swiss murine 3T3 fibroblasts with an EC50 of 100 nM and the proliferation of a number of human cancer cells. Site-directed mutagenesis of the active-site cysteines of thioredoxin has shown that redox activity is necessary for the stimulation of cell proliferation. Added 125I-thioredoxin is taken up by cells in culture and could have intracellular action. A series of alkyl 2-imidazolyl disulfides have been shown to be competitive inhibitors of human thioredoxin reductase with Ki values of 3.3 to 8.6 microM. The compounds inhibited Swiss 3T3 serum-dependent proliferation with IC50 values of 2.0 to 4.0 microM, and one compound inhibited Swiss 3T3 thioredoxin-dependent proliferation with an IC50 value of 60 nM.
Powis
G
G
Arizona Cancer Center, Tucson 85724, USA.
Oblong
J E
JE
Gasdaska
P Y
PY
Berggren
M
M
Hill
S R
SR
Kirkpatrick
D L
DL
D016475:3T3 Cells / Q000166:cytology; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D007457:Iodine Radioisotopes; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013268:Stimulation, Chemical; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase