Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53

Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53

^*Derald H. Ruttenberg Cancer Center and ^†Department of Pediatrics, Division of Hematology/Oncology, Mount Sinai School of Medicine New York, NY 10029; ^§Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea; and ^¶Department of Medicine, Beth Israel Hospital, Harvard Institutes of Medicine, Boston, MA 02115

Edited by Arnold J. Levine, Princeton University, Princeton, NJ, and approved June 30, 1997 (received for review April 7, 1997)

Abstract

The p53 tumor suppressor gene has been shown to play an important role in determining cell fate. Overexpression of wild-type p53 in tumor cells has been shown to lead to growth arrest or apoptosis. Previous studies in fibroblasts have provided indirect evidence for a link between p53 and senescence. Here we show, using an inducible p53 expression system, that wild-type p53 overexpression in EJ bladder carcinoma cells, which have lost functional p53, triggers the rapid onset of G₁ and G₂/M growth arrest associated with p21 up-regulation and repression of mitotic cyclins (cyclin A and B) and cdc2. Growth arrest in response to p53 induction became irreversible within 48-72 h, with cells exhibiting morphological features as well as specific biochemical and ultrastructural markers of the senescent phenotype. These findings provide direct evidence that p53 overexpression can activate the rapid onset of senescence in tumor cells.

Footnotes

↵ ‡ M.M.S. and D.Y.S. contributed equally to this work.
↵ ‖ To whom reprint requests should be addressed at: Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1130, New York, NY. e-mail: aaronson{at}smtplink.mssm.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: tet, tetracycline; wt, wild type; CAT, chloramphenicol acetyltransferase; SA–β-gal, senescence-associated β-galactosidase.