PML is induced by oncogenic ras and promotes premature senescence.
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.
Ferbeyre
G
G
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
de Stanchina
E
E
Querido
E
E
Baptiste
N
N
Prives
C
C
Lowe
S W
SW
D016922:Cellular Senescence / Q000502:physiology*; D011905:Genes, ras; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human