Journal
NATURE CELL BIOLOGY
Volume 8, Issue 8, Pages 877-U155Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1448
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Funding
- NIGMS NIH HHS [R01 GM057242, R01 GM057242-10, GM57242] Funding Source: Medline
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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(1-3). 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-GSK3 beta 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-GSK3 beta-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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