Preincubation with the proteasome inhibitor MG-132 enhances proteasome activity via the Nrf2 transcription factor in aging human skin fibroblasts

TY - JOUR

T1 - Preincubation with the proteasome inhibitor MG-132 enhances proteasome activity via the Nrf2 transcription factor in aging human skin fibroblasts

AU - Kraft, David Christian

AU - Deocaris, Custer C

AU - Wadhwa, Renu

AU - Rattan, Suresh I S

PY - 2006

Y1 - 2006

N2 - Strategies that lead to the upregulation of the proteasome are known to elicit beneficial consequences to the organism by countering oxidative stress-associated disorders, such as protein conformational diseases, cancer, and aging. Mild treatment with proteasome inhibitors has been previously demonstrated to stimulate proteasome activity and cellular resistance against oxidative injury. However, the mechanism for this action has not been clearly defined. We examined the role of the nuclear factor-E2-related factor 2 (Nrf2) in fibroblasts, a key transactivator of the antioxidant response pathway, in the regulation of the proteasome by its inhibitor MG-132. Here, we demonstrate that the stimulation of the proteasome by low levels of MG-132 can be abrogated by small interfering RNAs (siRNAs) targeted against Nrf2. Consistently, cells that constitutively express Nrf2 exhibit elevated levels of proteasome activities. We further investigate how its beneficial effects, that is, proteasome stimulation, are manifested in young and replicative-senescent cells. Our data underscore that manipulation of Nrf2 by the administration of pharmacologically low levels of proteasome inhibitors may prove to be an alternatively potent strategy for inducing long-term protective effects against oxidative stress.

AB - Strategies that lead to the upregulation of the proteasome are known to elicit beneficial consequences to the organism by countering oxidative stress-associated disorders, such as protein conformational diseases, cancer, and aging. Mild treatment with proteasome inhibitors has been previously demonstrated to stimulate proteasome activity and cellular resistance against oxidative injury. However, the mechanism for this action has not been clearly defined. We examined the role of the nuclear factor-E2-related factor 2 (Nrf2) in fibroblasts, a key transactivator of the antioxidant response pathway, in the regulation of the proteasome by its inhibitor MG-132. Here, we demonstrate that the stimulation of the proteasome by low levels of MG-132 can be abrogated by small interfering RNAs (siRNAs) targeted against Nrf2. Consistently, cells that constitutively express Nrf2 exhibit elevated levels of proteasome activities. We further investigate how its beneficial effects, that is, proteasome stimulation, are manifested in young and replicative-senescent cells. Our data underscore that manipulation of Nrf2 by the administration of pharmacologically low levels of proteasome inhibitors may prove to be an alternatively potent strategy for inducing long-term protective effects against oxidative stress.

KW - Cell Aging

KW - Cells, Cultured

KW - Dose-Response Relationship, Drug

KW - Enzyme Inhibitors

KW - Genes, Reporter

KW - Humans

KW - Leupeptins

KW - Luciferases

KW - NF-E2-Related Factor 2

KW - Proteasome Endopeptidase Complex

U2 - 10.1196/annals.1354.060

DO - 10.1196/annals.1354.060

M3 - Journal article

C2 - 16804021

SN - 0077-8923

VL - 1067

SP - 420

EP - 424

JO - New York Academy of Sciences. Annals

JF - New York Academy of Sciences. Annals

ER -