Tissue specific increase of the catalytic subunits of the 26S proteasome by indirect antioxidant dithiolethione in mice: enhanced activity for degradation of abnormal protein.
Decreases in the 26S proteasome are related to the toxicities of abnormal protein aggregates and may contribute to pathogenesis of degenerative diseases. Therefore, maintenance of proteasome function can be a novel strategy to protect cells against abnormal protein-mediated toxicity. In the present study, we have demonstrated the tissue specific increase of the catalytic subunits of the proteasome in mice following oral administration of 3H-1,2-dithiole-3-thione (D3T, 0.5 mmol/kg), which functions as a cancer preventive agent in animal and human studies. Expression of the 20S catalytic core subunits PSMB5, PSMB6, and PSMB7 were increased in liver, lung, small intestine, and colon of mice at 24 h after D3T treatment. Elevated expression of proteasome catalytic subunits led to increases in proteasomal peptidase activities in these tissues. Oral administration of D3T also exerted a pharmacodynamic action in some brain regions of these mice and proteasomal peptidase activities were significantly elevated in the cerebral cortex-hippocampus. Moreover, tissue extracts from D3T-treated mice and cell lysates obtained from D3T-incubated murine neuroblastoma cells exhibited the enhanced capacity to degrade mutant human SOD1G93A protein. These results indicate that the catalytic subunits of the 26S proteasome are inducible in multiple tissues of mouse including brain by exogenous chemical treatment. Increased proteasome expression by inducers may have a role in protection/attenuation of protein aggregate-mediated disorders.
Kwak
Mi-Kyoung
MK
College of Pharmacy, Yeungnam University, 214-1 Dae-Dong, Gyeongsan-Si, Gyeongsangbuk-Do, South Korea. mkwak@yumail.ac.kr
Huang
Bo
B
Chang
Hanna
H
Kim
Jung-Ae
JA
Kensler
Thomas W
TW
D000704:Analysis of Variance; D000781:Anethole Trithione / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D020134:Catalytic Domain / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D004926:Escherichia coli; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015151:Immunoblotting; D051379:Mice; D008813:Mice, Inbred ICR; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism
D017931:DNA Primers; D011506:Proteins; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase; D046988:Proteasome Endopeptidase Complex; C478802:Psmb5 protein, mouse; C061553:ATP dependent 26S protease; D000781:Anethole Trithione