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Vol. 14, No. 16, pp. 2015-2027, August 15, 2000
1 Cold Spring Harbor Laboratory, Cold Spring Harbor, New
York 11724 USA; 2 Department of Biological Sciences,
Columbia University, New York, New York 10027 USA
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.
[Key Words: senescence; ras; PML; p53; retinoblastoma protein; p16]
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