PML is induced by oncogenic ras and promotes premature senescence

G Ferbeyre, E de Stanchina, E Querido… - Genes & …, 2000 - genesdev.cshlp.org
G Ferbeyre, E de Stanchina, E Querido, N Baptiste, C Prives, SW Lowe
Genes & development, 2000genesdev.cshlp.org
Oncogenic ras provokes a senescent-like arrest in human diploid fibroblasts involving the
Rb and p53 tumor suppressor pathways. To further characterize this response, we
compared gene expression patterns between ras-arrested and quiescent IMR90 fibroblasts.
One of the genes up-regulated during ras-induced arrest was promyelocytic leukemia (PML)
protein, a potential tumor suppressor that encodes a component of nuclear structures known
as promyelocytic oncogenic domains (PODs). PML levels increased during both ras-induced …
Oncogenic ras provokes a senescent-like arrest in human diploid fibroblasts involving the Rb and p53 tumor suppressor pathways. To further characterize this response, we compared gene expression patterns between ras-arrested and quiescent IMR90 fibroblasts. One of the genes up-regulated during ras-induced arrest was promyelocytic leukemia (PML) protein, a potential tumor suppressor that encodes a component of nuclear structures known as promyelocytic oncogenic domains (PODs). PML levels increased during bothras-induced arrest and replicative senescence, leading to a dramatic increase in the size and number of PODs. Forced PMLexpression was sufficient to promote premature senescence. Like oncogenic ras, PML increased the levels of p16, hypophosphorylated Rb, phosphoserine-15 p53, and expression of p53 transcriptional targets. The fraction of Rb and p53 that colocalized with PML markedly increased during ras-induced arrest, and expression of PML alone forced p53 to the PODs. E1A abolishedPML-induced arrest and prevented PML induction and p53 phosphorylation in response to oncogenic ras. These results imply that PML acts with Rb and p53 to promote ras-induced senescence and provide new insights into PML regulation and activity.
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