Role of 2-5A-dependent RNase-L in senescence and longevity.
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<0.0001) longer than strain-matched RNase-L+/+ mice providing evidence for a physiological role for RNase-L in aging. These findings identify a novel role for RNase-L in senescence that may contribute to its tumor suppressive function and to the enhanced longevity of RNase-L-/- mice.
Andersen
J B
JB
Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA.
Li
X L
XL
Judge
C S
CS
Zhou
A
A
Jha
B K
BK
Shelby
S
S
Zhou
L
L
Silverman
R H
RH
Hassel
B A
BA
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D041702:BALB 3T3 Cells; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D025521:Tumor Suppressor Proteins; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease