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The ARF protein is a key mediator of the activation of the p53 tumor suppressor in response to excessive mitogenic signals. ARF is encoded in the INK4a/ARF locus, together with the cell-cycle inhibitor p16INK4a. Mice genetically deficient for ARF show a marked predisposition to tumor formation, supporting an important role for ARF in tumor protection. Alterations of the INK4a/ARF locus are a highly frequent event in human tumors. In some instances, the alterations in the locus result in specific inactivation of ARF. This review will summarise the current knowledge about the biological function and regulation of ARF, and will discuss the evidence from genetically modified murine models, and human tumors which supports a relevant role for ARF in tumor suppression.Peer Reviewe

The ARF protein in tumor suppression: lessons from mouse models and human tumors