Role of p14/p19ARF in Tumor Suppression

The INK4a [inhibitor of CDK (cyclin-dependent kinase) 4a]/ARF (alternative reading frame) tumor-suppressor locus encodes the ARF (p14ARF in humans and p19ARF in mice) protein. The ARF protein predominantly localizes in the nucleolus and its expression level is very low in both developing and adult tissues. ARF functions as a tumor suppressor by suppressing abnormal cell proliferation in response to high levels of oncogenic signals, resulting in cell-cycle arrest and/or apoptosis. This tumor-suppressive function can be mediated via a p53-dependent pathway and/or a p53-independent pathway. The well documented p53-dependent pathway model indicates that ARF responds to oncogenic signals and inhibits Mdm2-mediated ubiquitination of p53, resulting in p53 stabilization, cell-cycle arrest or apoptosis.ARF has also been shown to exert its function independently of p53. p14/19ARF can bind and inhibit the transcription factor E2F1, thereby interfering with the cell cycle progression. ARF can activate Rb, a known inhibitor of E2F1, thus reinforcing its inhibitory effect on cell cycle progression. Recent studies have described Arf as a negative regulator of ribosomal RNA processing. UBF, a protein required for the initiation of the transcriptional complex, has been shown to bind ARF. ARF binding to UBF results in hypophosphorylation of the latter, making UBF unable to efficiently recruit the transcription complex. This change in the phosphorylation status of UBF leads to a reduction of 47S rRNA transcription. ARF also represses the transcription of RNA polymerase III leading to an inhibition of tRNA synthesis. Another means by which ARF effects inhibition of ribosome biogenesis is by controlling the subnuclear localization of the RNA polymerase I transcription termination factor, TTF-I. TTF-I shuttles between nucleoplasm and nucleolus with the aid of the chaperone NPM/B23 and a nucleolar localization sequence within its N-terminal regulatory domain. ARF inhibits nucleolar import of TTF-I by binding to this nucleolar localization sequence, causing the accumulation of TTF-I in the nucleoplasm. ARF also promotes the degradation of NPM, further enhancing its negative effect on ribosome biogenesis. Arf triggers a rapid proteasomal degradation of Senp3, the SUMO-2/3 deconjugating protease. This is another example of the p53-independent tumor suppressive function of Arf where ARF antagonizes Senp3, thereby inducing cell cycle arrest by abnormally elevating the cellular levels of SUMOylated proteins.