Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis.
Thioredoxin is a major component of thiol-reducing system. Recently, we identified thioredoxin-binding protein-2 (TBP-2) as a negative regulator of thioredoxin. Here, we report the role of TBP-2 in oxidative renal tubular injury and the subsequent carcinogenesis by ferric nitrilotriacetate. TBP-2 was abundantly expressed in the rat kidney. Immunohistochemical analysis revealed that TBP-2 was present in association with nuclei and mitochondrial intermembrane space in the proximal tubular cells and coimmunoprecipitated with cytochrome c. After acute oxidative tubular damage, TBP-2 protein, but not messenger RNA, markedly decreased, demonstrating shortened half-life of this protein. Most cases of the induced renal cell carcinoma showed undetectable levels of TBP-2 protein, which was associated with the methylation of CpG island in the promoter region. Genome sequence analyses identified the poly-A tract in the 3' untranslated region as a mutation hot spot in this rather nonselective environment. Collectively, the amounts of TBP-2 protein were inversely associated with proliferation of tubular cells, as evaluated by proliferating cell nuclear antigen. These results suggest that loss of TBP-2 is essential for proliferation of not only neoplastic but also non-neoplastic renal tubular cells, and that TBP-2 is a target gene in oxidative stress-induced renal carcinogenesis by ferric nitrilotriacetate.
Dutta
Khokon K
KK
Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nishinaka
Yumiko
Y
Masutani
Hiroshi
H
Akatsuka
Shinya
S
Aung
Than T
TT
Shirase
Tomoyuki
T
Lee
Wen-Hua
WH
Yamada
Yoshihiro
Y
Hiai
Hiroshi
H
Yodoi
Junji
J
Toyokuni
Shinya
S
D000818:Animals; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002455:Cell Division; D004252:DNA Mutational Analysis; D017931:DNA Primers; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009571:Nitrilotriacetic Acid; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D017931:DNA Primers; D012333:RNA, Messenger; C493796:TXNIP protein, rat; D009571:Nitrilotriacetic Acid