Mutational analysis of human thioredoxin reductase 1. Effects on p53-mediated gene expression and interferon and retinoic acid-induced cell death.
The interferon (IFN)-beta and all-trans-retinoic acid combination suppresses tumor growth by inducing apoptosis in several tumor cell lines. A genetic technique permitted the isolation of human thioredoxin reductase (TR) as a critical regulator of IFN/all-trans-retinoic acid-induced cell death. Our recent studies have shown that TR1:thioredoxin 1-regulated cell death is effected in part through the activation of p53-dependent responses. To understand its death regulatory function, we have performed a mutational analysis of TR. Human TR1 has three major structural domains, the FAD binding domain, the NADPH binding domain, and an interface domain (ID). Here, we show that the deletion of the C-terminal interface domain results in a constitutive activation of TR-dependent death responses and promotes p53-dependent gene expression. TR mutant without the ID still retains its dependence on thioredoxin for promoting these responses. Thus, our data suggest that TR-ID acts as a regulatory domain.
Ma
Xinrong
X
Greenebaum Cancer Center, Department of Microbiology & Immunology, Molecular and Cellular Biology Program, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Hu
Junbo
J
Lindner
Daniel J
DJ
Kalvakolanu
Dhananjaya V
DV
D001483:Base Sequence; D015153:Blotting, Western; D016923:Cell Death; D002455:Cell Division; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics* / Q000502:physiology*; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D016159:Tumor Suppressor Protein p53; D009249:NADP; D014212:Tretinoin; D016899:Interferon-beta; D007372:Interferons; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase