Role of 2-5A-dependent RNase-L in senescence and longevity

TY - JOUR

T1 - Role of 2-5A-dependent RNase-L in senescence and longevity

AU - Andersen, Jesper Bøje

AU - Li, X L

AU - Judge, C S

AU - Zhou, A

AU - Jha, B K

AU - Shelby, S

AU - Zhou, L

AU - Silverman, R H

AU - Hassel, B A

PY - 2007/5/10

Y1 - 2007/5/10

N2 - Senescence is a permanent growth arrest that restricts the lifespan of primary cells in culture, and represents an in vitro model for aging. Senescence functions as a tumor suppressor mechanism that can be induced independent of replicative crisis by diverse stress stimuli. RNase-L mediates antiproliferative activities and functions as a tumor suppressor in prostate cancer, therefore, we examined a role for RNase-L in cellular senescence and aging. Ectopic expression of RNase-L induced a senescent morphology, a decrease in DNA synthesis, an increase in senescence-associated beta-galactosidase activity, and accelerated replicative senescence. In contrast, senescence was retarded in RNase-L-null fibroblasts compared with wild-type fibroblasts. Activation of endogenous RNase-L by 2-5A transfection induced distinct senescent and apoptotic responses in parental and Simian virus 40-transformed WI38 fibroblasts, respectively, demonstrating cell type specific differences in the antiproliferative response to RNase-L activation. Replicative senescence is a model for in vivo aging; therefore, genetic disruption of senescence effectors may impact lifespan. RNase-L-/- mice survived 31.7% (P

AB - Senescence is a permanent growth arrest that restricts the lifespan of primary cells in culture, and represents an in vitro model for aging. Senescence functions as a tumor suppressor mechanism that can be induced independent of replicative crisis by diverse stress stimuli. RNase-L mediates antiproliferative activities and functions as a tumor suppressor in prostate cancer, therefore, we examined a role for RNase-L in cellular senescence and aging. Ectopic expression of RNase-L induced a senescent morphology, a decrease in DNA synthesis, an increase in senescence-associated beta-galactosidase activity, and accelerated replicative senescence. In contrast, senescence was retarded in RNase-L-null fibroblasts compared with wild-type fibroblasts. Activation of endogenous RNase-L by 2-5A transfection induced distinct senescent and apoptotic responses in parental and Simian virus 40-transformed WI38 fibroblasts, respectively, demonstrating cell type specific differences in the antiproliferative response to RNase-L activation. Replicative senescence is a model for in vivo aging; therefore, genetic disruption of senescence effectors may impact lifespan. RNase-L-/- mice survived 31.7% (P

KW - Aging

KW - Animals

KW - BALB 3T3 Cells

KW - Cell Aging

KW - Cell Line, Transformed

KW - Cells, Cultured

KW - Endoribonucleases

KW - Longevity

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Tumor Suppressor Proteins

U2 - 10.1038/sj.onc.1210111

DO - 10.1038/sj.onc.1210111

M3 - Journal article

C2 - 17130839

SN - 0950-9232

VL - 26

SP - 3081

EP - 3088

JO - Oncogene

JF - Oncogene

IS - 21

ER -