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      Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence.

      Nature cell biology

      Animals, Blotting, Western, Cell Aging, genetics, physiology, Cell Proliferation, drug effects, Cells, Cultured, Cisplatin, pharmacology, Cyclin-Dependent Kinase 4, metabolism, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, Embryo, Mammalian, cytology, Fibroblasts, Glycogen Synthase Kinase 3, Humans, Mice, Microscopy, Fluorescence, Mutation, NIH 3T3 Cells, Phosphatidylinositol 3-Kinases, Plasminogen Activator Inhibitor 1, Proto-Oncogene Proteins c-akt, RNA Interference, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53

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          Abstract

          p53 limits the proliferation of primary diploid fibroblasts by inducing a state of growth arrest named replicative senescence - a process which protects against oncogenic transformation and requires integrity of the p53 tumour suppressor pathway. However, little is known about the downstream target genes of p53 in this growth-limiting response. Here, we report that suppression of the p53 target gene encoding plasminogen activator inhibitor-1 (PAI-1) by RNA interference (RNAi) leads to escape from replicative senescence both in primary mouse embryo fibroblasts and primary human BJ fibroblasts. PAI-1 knockdown results in sustained activation of the PI(3)K-PKB-GSK3beta pathway and nuclear retention of cyclin D1, consistent with a role for PAI-1 in regulating growth factor signalling. In agreement with this, we find that the PI(3)K-PKB-GSK3beta-cyclin D1 pathway is also causally involved in cellular senescence. Conversely, ectopic expression of PAI-1 in proliferating p53-deficient murine or human fibroblasts induces a phenotype displaying all the hallmarks of replicative senescence. Our data indicate that PAI-1 is not merely a marker of senescence, but is both necessary and sufficient for the induction of replicative senescence downstream of p53.

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          Journal
          16862142
          2954492
          10.1038/ncb1448

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