ARF Tumor Suppressor - SmARF

SmARF

Until recently, the two known effects of ARF were growth inhibition by NPM interactions and apoptosis induction by Mdm2 interactions. The function of ARF involving p53-independent death, has now been attributed to the small mitochondrial isoform of ARF, smARF. While full-length ARF inhibits cell growth by cell cycle arrest or type I apoptotic death, smARF kills cells by type II autophagic death. Like ARF, the expression of smARF increases when there are aberrant proliferation signals. When smARF is overexpressed, it localizes to the mitochondrial matrix, damaging the mitochondria membrane potential and structure, and leading to autophagic cell death.

The translation of the truncated ARF, smARF, is initiated at an internal methionine (M45) of the ARF transcript in human and mouse cells. SmARF is also detected in rat, even though an internal methionine is not present in the rat transcript. This suggests that there is an alternate mechanism to form smARF, underscoring the importance of this isoform. The role of smARF is distinct from that of ARF, as it lacks the nuclear localization signal (NLS) and cannot bind to Mdm2 or NPM. In some cell types, however, full-length ARF can also localize to the mitochondria and induce type II cell death, suggesting that in addition to autophagy being a starvation or other environmental response, it may also be involved in responding to oncogene activation.