Tumor Suppressor Arf Inhibits Ribosomal Biogenesis
| PAG Title | Tumor Suppressor Arf Inhibits Ribosomal Biogenesis |
| PAG ID | WIG000259 |
| Type | P |
| Source Link |  MSigDB |
| Publication Reference | NA |
| PAG Description | Cyclin-dependent kinase inhibitor-2A (CDKN2A) goes by the colloquial designation p16, which is sometimes referred to as p16(INK4). The alpha transcript of CDKN2A has been shown to encode p16(INK4a), a recognized tumor suppressor that induces a G1 cell cycle arrest by inhibiting the phosphorylation of the RB protein by the cyclin-dependent kinases CDK4 and CDK6. The beta transcript of CDKN2A encodes p14(ARF). The predicted 132-amino acid p14(ARF) is shorter than the corresponding mouse protein, p19(ARF), and the 2 proteins share only 50% identity. However, both proteins have the ability to elicit a p53 response, manifest in the increased expression of both CDKN1A and MDM2, and resulting in a distinctive cell cycle arrest in both the G1 and G2/M phases. Two unrelated proteins encoded by the INK4A-ARF locus function in tumor suppression. ARF binds to MDM2 and promotes the rapid degradation of MDM2. This interaction is mediated by the E1-beta-encoded N-terminal domain of ARF and a C-terminal region of MDM2. ARF-promoted MDM2 degradation is associated with MDM2 modification and concurrent p53 stabilization and accumulation. The p19(Arf) tumor suppressor inhibits production of ribosomal RNA, retarding processing of 47/45S and 32S precursors. These effects correlate with but do not strictly depend upon inhibition of rRNA biosynthesis or cell cycle arrest, are not mimicked by p53, and require neither p53 nor Mdm2. Arf mutants lacking conserved amino acid residues 2-14 do not block rRNA synthesis and processing or inhibit cell proliferation. Evolution may have linked a primordial nucleolar Arf function to Mdm2 and p53, creating a more efficient checkpoint-signaling pathway for coordinating ribosomal biogenesis and cell cycle progression. |
| Species | Homo sapiens |
| Quality Metric Scores | nCoCo Score: 1,013 |
| Information Content | Rich |
| Other IDs | M11358 |
| Base PAG ID | WIG000259 |
| Human Phenotyte Annotation | |
| Curator | PAGER curation team |
| Curator Contact | PAGER-contact@googlegroups.com |
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