Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis.

Abstract

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.

• Authors: Khokon K Dutta, Yumiko Nishinaka, Hiroshi Masutani, Shinya Akatsuka, Than T Aung, Tomoyuki Shirase, Wen-Hua Lee, Yoshihiro Yamada, Hiroshi Hiai, Junji Yodoi, Shinya Toyokuni
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 85 Issue 6 Pg. 798-807 (Jun 2005) ISSN: 0023-6837 [Print] United States
• PMID: 15834431 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Cell Cycle Proteins
• DNA Primers
• RNA, Messenger
• TXNIP protein, rat
• Nitrilotriacetic Acid

Topics

• Animals
• Base Sequence
• Carcinoma, Renal Cell (chemically induced, genetics, pathology)
• Carrier Proteins (genetics)
• Cell Cycle Proteins
• Cell Division
• DNA Mutational Analysis
• DNA Primers
• Kidney Neoplasms (chemically induced, genetics, pathology)
• Male
• Molecular Sequence Data
• Nitrilotriacetic Acid
• Oxidative Stress
• RNA, Messenger (genetics)
• Rats
• Rats, Wistar