The study investigates the effects of oncogenic Raf on the senescence of human fibroblasts. Using conditionally active forms of Raf-1, the researchers found that activation of Raf led to irreversible cell cycle arrest and premature senescence in IMR-90 human lung fibroblasts. This senescence was accompanied by the induction of cyclin-dependent kinase (CDK) inhibitors p21Cip1 and p16Ink4a, but not p53. The induction of p16Ink4a was sufficient to elicit senescence when expressed ectopically. Pharmacological inhibition of the Raf/MEK/MAP kinase cascade prevented Raf-induced senescence, suggesting that this pathway is crucial for the process. The results indicate that oncogenic Raf can induce senescence, which may serve as a defense mechanism against neoplastic transformation when the MAP kinase signaling cascade is inappropriately active.The study investigates the effects of oncogenic Raf on the senescence of human fibroblasts. Using conditionally active forms of Raf-1, the researchers found that activation of Raf led to irreversible cell cycle arrest and premature senescence in IMR-90 human lung fibroblasts. This senescence was accompanied by the induction of cyclin-dependent kinase (CDK) inhibitors p21Cip1 and p16Ink4a, but not p53. The induction of p16Ink4a was sufficient to elicit senescence when expressed ectopically. Pharmacological inhibition of the Raf/MEK/MAP kinase cascade prevented Raf-induced senescence, suggesting that this pathway is crucial for the process. The results indicate that oncogenic Raf can induce senescence, which may serve as a defense mechanism against neoplastic transformation when the MAP kinase signaling cascade is inappropriately active.