Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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4-Hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress. Identification of proteasomes as target molecules

Okada K., Wangpoengtrakul C., Osawa T., Toyokuni S., Tanaka K., Uchida K.

Journal of Biological Chemistry Vol. 274 ( 34 ) page： 23787 - 23793 1999.8

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Biological Chemistry

Oxidative stress is associated with important pathophysiological events in a variety of diseases. It has been postulated that free radicals and lipid peroxidation products generated during the process may be responsible for these effects because of their ability to damage cellular components such as membranes, proteins, and DNA. In the present study, we provide evidence that oxidative stress causes a transient impairment of intracellular proteolysis via covalent binding of 4-hydroxy-2-nonenal (HNE), a major end product of lipid peroxidation, to proteasomes. A single intraperitoneal treatment with the renal carcinogen, ferric nitrilotriacetate, caused oxidative stress, as monitored by accumulation of lipid peroxidation products and 8-hydroxy-2'- deoxyguanosine, in the kidney of mice. In addition, transient accumulation of HNE-modified proteins in the kidney was also found by competitive enzyme- linked immunosorbent assay and immunohistochemical analyses. This and the observation that the HNE-modified proteins were significantly ubiquitinated suggested a crucial role of proteasomes in the metabolism of HNE-modified proteins. In vitro incubation of the kidney homogenates with HNE indeed resulted in a transient accumulation of HNE-modified proteins, whereas the proteasome inhibitor significantly suppressed the time-dependent elimination of HNE-modified proteins. We found that, among three proteolytic activities (trypsin, chymotrypsin, and peptidylglutamyl peptide hydrolase activities) of proteasomes, both trypsin and peptidylglutamyl peptide hydrolase activities in the kidney were transiently diminished in accordance with the accumulation of HNE-modified proteins during oxidative stress. The loss of proteasome activities was partially ascribed to the direct attachment of HNE to the protein, based on the detection of HNE-proteasome conjugates by an immunoprecipitation technique. These results suggest that HNE may contribute to the enhanced accumulation of oxidatively modified proteins via an impairment of ubiquitin/proteasome-dependent intracellular proteolysis.

DOI： 10.1074/jbc.274.34.23787

Scopus

Persistent oxidative stress in human colorectal carcinoma, but not in adenoma

Kondo S, Toyokuni S, Iwasa Y, Tanaka T, Onodera H, Hiai H, Imamura M

FREE RADICAL BIOLOGY AND MEDICINE Vol. 27 ( 3-4 ) page： 401 - 410 1999.8

Persistent oxidative stress in human colorectal carcinoma, but not in adenoma

Kondo S., Toyokuni S., Iwasa Y., Tanaka T., Onodera H., Hiai H., Imamura M.

Free Radical Biology and Medicine Vol. 27 ( 3-4 ) page： 401 - 410 1999.8

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Free Radical Biology and Medicine

Few studies have been conducted focusing on a potential role of reactive oxygen species in tumor cell metabolism. Here we studied human colorectal adenocarcinomas and adenomas to determine whether oxidative stress is imposed on cancer cells in vivo and used specific antibodies against 8-hydroxy-2'- deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE)-modified proteins, and 3- nitro-L-tyrosine (3-NT) to determine whether there is an association between oxidative stress and cellular proliferation. Higher levels of oxidative modifications in DNA and proteins were observed in carcinoma cells, but not in adenoma cells, than in the corresponding nontumorous epithelial cells by immunohistochemistry as well as high-performance liquid chromatography (HPLC)-based 8-OHdG determination. The fraction of proliferating cell nuclear antigen-positive cells was proportionally associated in adenocarcinomas with the staining intensities of 8-OHdG and 3-NT. Furthermore, Western blot analysis of the proteins extracted from carcinoma cells revealed several specific proteins modified by HNE or peroxynitrite. Thus we concluded that colorectal carcinoma, but not adenoma cells, are exposed to more oxidative stress than their corresponding nontumorous epithelial cells, regardless of clinical stage and histology, and further that the oxidative stress in carcinoma cells might stimulate cellular proliferation.

DOI： 10.1016/S0891-5849(99)00087-8

Scopus

The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-hydroxy-2 '-deoxyguanosine in arsenic-related Bowen's disease

Matsui M, Nishigori C, Toyokuni S, Takada J, Akaboshi M, Ishikawa M, Imamura S, Miyachi Y

JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 113 ( 1 ) page： 26 - 31 1999.7

The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-hydroxy-2 '-deoxyguanosine in arsenic-related Bowen's disease

Matsui M, Nishigori C, Toyokuni S, Takada J, Akaboshi M, Ishikawa M, Imamura S, Miyachi Y

JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 113 ( 1 ) page： 26 - 31 1999.7

High incidence of allelic loss on chromosome 5 and inactivation of p15(INK4B) and p16(INK4A) tumor suppressor genes in oxystress-induced renal cell carcinoma of rats

Tanaka T, Iwasa Y, Kondo S, Hiai H, Toyokuni S

ONCOGENE Vol. 18 ( 25 ) page： 3793 - 3797 1999.6

High incidence of allelic loss on chromosome 5 and inactivation of p15(INK4B) and p16(INK4A) tumor suppressor genes in oxystress-induced renal cell carcinoma of rats

Tanaka T., Iwasa Y., Kondo S., Hiai H., Toyokuni S.

Oncogene Vol. 18 ( 25 ) page： 3793 - 3797 1999.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Oncogene

Ferric nitrilotriacetate induces oxidative damage in renal proximal tubules, a consequence of Fenton-like reaction, that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. In order to find common genetic alterations in this oxystress-induced carcinogengesis model, RCCs were produced in F1 hybrid rats between Wistar and Long-Evans strains and genomes were screened for loss of heterozygosity (LOH) with microsatellite polymorphic markers by PCR. Five consecutive markers on chromosome 5 (D5Mgh5, D5Mit9, D5Mgh6, D5Mit11 and D5Mit6) showed LOH in ≥ 40% of the RCCs. As possible candidate tumor suppressor genes on chromosome 5, p15(INK4B) and p16(INK4A) were investigated for genetic alteration and aberrant methylation by Southern blot, PCR/SSCP/sequencing and methylation-specific PCR. Genetic alteration (homozygous or hemizygous deletion with or without point mutation) or aberrant methylation were found in 30.7 and 53.8% of the RCC cases, respectively, which was proportionally associated with the histological nuclear grade and metastatic activity. Our data suggest that inactivation of p15 and p16 genes could be one of the major pathways responsible for oxystress-induced carcinogenesis.

DOI： 10.1038/sj.onc.1202707

Scopus

High incidence of allelic loss on chromosome 5 and inactivation of p15(INK4B) and p16(INK4A) tumor suppressor genes in oxystress-induced renal cell carcinoma of rats

Tanaka T, Iwasa Y, Kondo S, Hiai H, Toyokuni S

ONCOGENE Vol. 18 ( 25 ) page： 3793 - 3797 1999.6

A 1-hour enzyme-linked immunosorbent assay for quantitation of acrolein- and hydroxynonenal-modified proteins by epitope-bound casein matrix method Reviewed International journal

Satoh K, Yamada S, Koike Y, Igarashi Y, Toyokuni S, Kumano T, Takahata T, Hayakari M, Tsuchida S, Uchida K

ANALYTICAL BIOCHEMISTRY Vol. 270 ( 2 ) page： 323 - 328 1999.6

A 1-hour enzyme-linked immunosorbent assay for quantitation of acrolein- and hydroxynonenal-modified proteins by epitope-bound casein matrix method

Satoh K., Yamada S., Koike Y., Igarashi Y., Toyokuni S., Kumano T., Takahata T., Hayakari M., Tsuchida S., Uchida K.

Analytical Biochemistry Vol. 270 ( 2 ) page： 323 - 328 1999.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Analytical Biochemistry

A simple and rapid enzyme-linked immunosorbent assay (ELISA) method for quantitation of acrolein and 4-hydroxy-2-nonenal (HNE)-modified proteins was developed. Microtiter plate wells were precoated and blocked simultaneously with epitope-bound bovine caseins as matrix proteins, and aldehyde-modified proteins were quantitated by a competition assay with a monoclonal antibody specific for acrolein-modified lysine or HNE-modified histidine epitopes. Minimal reaction times required for the coating/blocking; first monoclonal antibody and the peroxidase-conjugated second antibody binding steps were 3, 3, and 7 min, respectively, the former two steps being found to be or akin to diffusion-rate-limiting reactions. The convenient ELISA should find an application for analyses of the intricate processes involved in oxidative stress and carcinogenic insult. The epitope-attachment methodology may also be advantageous for the quantitation of various other biologically important haptenic molecules.

DOI： 10.1006/abio.1999.4073

Scopus

A 1-hour enzyme-linked immunosorbent assay for quantitation of acrolein- and hydroxynonenal-modified proteins by epitope-bound casein matrix method Reviewed International journal

Satoh K, Yamada S, Koike Y, Igarashi Y, Toyokuni S, Kumano T, Takahata T, Hayakari M, Tsuchida S, Uchida K

ANALYTICAL BIOCHEMISTRY Vol. 270 ( 2 ) page： 323 - 328 1999.6

Intranuclear distribution of 8-hydroxy-2 '-deoxyguanosine: An immunocytochemical study

Toyokuni S, Iwasa Y, Kondo S, Tanaka T, Ochi H, Hiai H

JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY Vol. 47 ( 6 ) page： 833 - 835 1999.6

Intranuclear distribution of 8-hydroxy-2'-deoxyguanosine: An immunocytochemical study

Toyokuni S., Iwasa Y., Kondo S., Tanaka T., Ochi H., Hiai H.

Journal of Histochemistry and Cytochemistry Vol. 47 ( 6 ) page： 833 - 835 1999.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Histochemistry and Cytochemistry

We used immunofluorescence staining (monoclonal antibody N45.1) with cytological imprinting to study changes in the intranuclear distribution of 8-hydroxy-2'-deoxyguanosine in renal cells of male Wistar rats after oxidative stress by ferric nitrilotriacetate. In the control proximal tubule cells, small spherical signals were uniformly distributed throughout the nuclei. Under oxidative stress, immunofluorescence intensity was increased, especially near nuclear membrane. In cells with nuclear shrinkage or deformity, intense, diffuse signals throughout the nuclei were observed. Our results suggest that specific nuclear sites are vulnerable to oxidative DNA damage and that diffuse intense signals precede cell death after oxidative stress.

DOI： 10.1177/002215549904700613

Scopus

Intranuclear distribution of 8-hydroxy-2'-deoxyguanosine. An immunocytochemical study

TOYOKUNI S.

J Histochem Cytochem Vol. 47 ( 6 ) page： 833 - 835 1999.6

Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes Reviewed International journal

Ihara Y, Toyokuni S, Uchida K, Odaka H, Tanaka T, Ikeda H, Hiai H, Seino Y, Yamada Y

DIABETES Vol. 48 ( 4 ) page： 927 - 932 1999.4

Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes Reviewed International journal

IHARA Y

Diabetes Vol. 48 ( 4 ) page： 927 - 932 1999.4

Reactive oxygen species-induced molecular damage and its application in pathology

Toyokuni S.

Pathology International Vol. 49 ( 2 ) page： 91 - 102 1999.3

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Pathology International

Recent studies have clarified that reactive oxygen species (ROS) are involved in a diversity of biological phenomena including radiation damage, carcinogenesis, ischemia-reperfusion injury, diabetes mellitus and neurodegenerative diseases. The breakthrough of these fruitful accomplishments was the discovery of an enzyme, superoxide dismutase, by McCord and Fridovich in 1968. In the 1970s and 80s, biochemists and radiation biologists were attracted by the role of ROS in its irreversible damage to biological molecules. In the 1990s, ROS were further found to be a reversible modulator of protein structure as well, and this led to a recent rapid data accumulation on the association of ROS and transcription factors. At the same time, methods to localize ROS-induced damage in paraffin-embedded tissues have been established. This owes to a successful production of antibodies against covalently modified structures specific for ROS-induced damage. The epitopes include 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins. The present article reviews histochemical and immunohistochemical methods to localize ROS-induced damage in tissues and cells, further comments on the association of ROS with transcription factors, and shows a prospective view of ROS-induced carcinogenesis.

DOI： 10.1046/j.1440-1827.1999.00829.x

Scopus

Formation of 4-hydroxy-2-nonenal-modified proteins and 3-nitro-L-tyrosine in rat island skin flaps during and after ischemia Reviewed International journal

Um SC, Suzuki S, Toyokuni S, Uchida K, Hiai H, Nishimura Y

ANNALS OF PLASTIC SURGERY Vol. 42 ( 3 ) page： 293 - 298 1999.3

Protection of ischemia-reperfusion lung against oxidative stress by nitroglycerin.

Kawashima, M; Bando, T; Nakamura, T; Yoshimura, T; Hanaoka, N; Hirata, T; Fukuse, T; Hasegawa, S; Toyokuni, S; Hitomi, S; Wada, H

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Vol. 159 ( 3 ) page： A543 - A543 1999.3

Protection of ischemia-reperfusion lung against oxidative stress by nitroglycerin.

Kawashima M, Bando T, Nakamura T, Yoshimura T, Hanaoka N, Hirata T, Fukuse T, Hasegawa S, Toyokuni S, Hitomi S, Wada H

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Vol. 159 ( 3 ) page： A543 - A543 1999.3

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