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[Cancer Research 59, 2464-2469, May 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 2464-2469, May 15, 1999]
© 1999 American Association for Cancer Research

Molecular Biology and Genetics

Loss of the ARF Tumor Suppressor Reverses Premature Replicative Arrest but not Radiation Hypersensitivity Arising from Disabled Atm Function1

Takehiko Kamijo, Esther van de Kamp, Miriam J. Chong, Frederique Zindy, J. Alan Diehl, Charles J. Sherr2 and Peter J. McKinnon

Howard Hughes Medical Institute [T. K., J. A. D., C. J. S.[, and Departments of Tumor Cell Biology [T. K., E. v. d. K., F. Z., J. A. D., C. J. S.] and Genetics [M. J. C., P. J. M.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105

The alternative reading frame product (p19ARF) of the mouse INK4a/ARF locus is induced by oncoproteins such as Myc and E1A as part of a checkpoint response that limits cell cycle progression in response to hyperproliferative signals. ARF binds directly to Mdm2 to prevent down-regulation of p53 and thereby promotes p53-dependent transcription and cell cycle arrest. However, ARF is not required for p53 induction in response to ionizing radiation or other forms of DNA damage. Animals lacking a functional ataxia telangiectasia (Atm) gene are exquisitely sensitive to ionizing radiation; Atm-null mouse embryo fibroblasts (MEFs) undergo premature replicative arrest, which is relieved by the loss of p53. Here we show that the loss of ARF expands the life expectancy of Atm-null MEFs, but alters neither the sensitivity of Atm-null mice to ionizing radiation nor their propensity to develop lymphomas early in life. Therefore, whereas ARF and Atm signal to p53 through distinct pathways, the loss of ARF can modify p53-dependent features of the Atm-null phenotype.




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Copyright © 1999 by the American Association for Cancer Research.