Senescence is a permanent growth arrest that functions as a tumor suppressor mechanism. RNase-L mediates the antiviral, antiproliferative, and proapoptotic activities of interferon, and is implicated as a tumor suppressor in prostate cancer; therefore, we examined a role for RNase-L in cellular senescence. Ectopic expression of RNase-L resulted in the induction of a senescent morphology, a decreased mitotic index, increased senescence-associated β -galactosidase staining, and accelerated replicative senescence. In contrast, senescence was retarded in murine embryonic fibroblasts with a targeted disruption in the RNase-L gene. Remarkably, activation of endogenous RNase-L by 2-5A transfection induced distinct senescent and apoptotic responses in parental and SV40-transformed WI38 fibroblasts respectively demonstrating cell type specific differences in the antiproliferative phenotype induced by RNase-L activation. Analysis of gene expression following 2-5A transfection identified both up- and downregulated transcripts that encoded known and novel senescence effectors. These findings identify RNase-L as a novel regulator of senescence, a function that may contribute to its tumor suppressive activity.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]