ARF in the mitochondria: the last frontier?

The tumor suppressor ARF carries out different functions in different cellular compartments. In the nucleus, ARF interacts physically and functionally with Mdm2 to inhibit cell cycle progression through activation of p53. In the nucleolus, ARF interacts with B23/NPM to inhibit ribosomal biogenesis through control of rRNA processing. Recent studies have expanded ARF's territory into the mitochondria. New data have shown that ARF interacts with the mitochondrial protein p32/C1QBP and that the interaction is critical in order for ARF to localize to the mitochondria and induce apoptosis. Remarkably, the ARF-p32 interaction, and hence ARF's pro-apoptotic function, can be interrupted by human cancer-derived mutations in exon2 of the p14(ARF)-p16(INK4a) gene locus. Here, we discuss the implications of these studies and their potential relevance to human cancer.