Showing papers by "Elisa de Stanchina published in 2000"

PML is induced by oncogenic ras and promotes premature senescence

Abstract: 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 arrest and replicative senescence, leading to a dramatic increase in the size and number of PODs Forced PML expression 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 abolished PML-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