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Cellular senescence is an irreversible cell cycle arrest triggered by the activation of oncogenes or mitogenic signaling as well as the enforced expression of tumor suppressors such as p53, p16 INK4A and promyelocytic leukemia protein (PML) in normal cells. E2F-binding protein 1 (E2FBP1), a transcription regulator for E2F, induces PML reduction and suppresses the formation of PML-nuclear bodies, whereas the down-regulation of E2FBP1 provokes the PML-dependent premature senescence in human normal fibroblasts. Here we report that the depletion of E2FBP1 induces the accumulation of PML through the Ras-dependent activation of MAP kinase signaling. The cellular levels of p16 INK4A and p53 are elevated during premature senescence induced by depletion of E2FBP1, and the depletion of p16 INK4A , but not p53 rescued senescent cells from growth arrest. Therefore, the premature senescence induced by E2FBP1 depletion is achieved through the p16 INK4A -Rb pathway. Similar to human normal fibroblasts, the growth inhibition induced by E2FBP1 depletion is also observed in human tumor cells with intact p16 INK4A and Rb. These results suggest that E2FBP1 functions as a critical antagonist to the p16 INK4A -Rb tumor suppressor machinery by regulating PML stability.
Cellular senescence is an irreversible cell cycle arrest triggered by the activation of oncogenes or mitogenic signaling as well as the enforced expression of tumor suppressors such as p53, p16 INK4A and promyelocytic leukemia protein (PML) in normal cells. E2F-binding protein 1 (E2FBP1 ), a transcription regulator for E2F, induces PML reduction and suppresses the formation of PML-nuclear bodies, and the down-regulation of E2FBP1 provokes the PML-dependent premature senescence in human normal fibroblasts. Here we report that the depletion of E2FBP1 induces the accumulation of PML through the Ras-dependent activation of MAP kinase signaling. The cellular levels of p16 INK4A and p53 are elevated during premature senescence induced depletion of E2FBP1, and the depletion of p16 INK4A, but not p53 rescued senescent cells from growth arrest. Thus, the premature senescence induced by E2FBP1 depletion is achieved through the p16 INK4A -Rb pathway. Similar to human normal fibroblast s, the growth inhibition induced by E2FBP1 depletion is also observed in human tumor cells with intact p16 INK4A and Rb. These results suggest that E2FBP1 functions as a critical antagonist to the p16 INK4A -Rb tumor suppressor machinery by regulating PML stability.