Loss of the ARF tumor suppressor reverses premature replicative arrest butnot radiation hypersensitivity arising from disabled Atm function

The alternative reading frame product (p19(ARF)) of the mouse INK4a/ARF loc us is induced by oncoproteins such as Myc and E1A as part of a checkpoint r esponse that limits cell cycle progression in response to hyperproliferativ e signals. ARF binds directly to Mdm2 to prevent down-regulation of p53 and thereby promotes p53-dependent transcription and cell cycle arrest. Howeve r, ARF is not required for p53 induction in response to ionizing radiation or other forms of DNA damage. Animals Lacking a functional ataxia telangiec tasia (Ann) 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 lympho mas early in life. Therefore, whereas ARF and Atm signal to p53 through dis tinct pathways, the loss of ARF can modify p53-dependent features of the At m-null phenotype.