Role in Disease
Very commonly, cancer is associated with a loss of function of INK4a, ARF, Rb, or p53. Without INK4a, Cdk4/6 can inappropriately phosphorylate Rb, leading to increased E2F-dependent transcription. Without ARF, Mdm2 can inappropriately inhibit p53, leading to increased cell survival.
The tumor suppressor p53 is mutated in more than 50% of human cancers, and HDM2 is overexpressed in 5-10% of tumors. The INK4a/ARF locus is found to be deleted or silenced in many kinds of tumors. For example, of the 100 primary breast carcinomas, approximately 41% have p14ARF defects. In a separate study, 32% of colorectal adenomas (non-cancerous tumors) were found to have p14ARF inactivation due to hypermethylation of the promoter. Mouse models lacking p19Arf, p53, and Mdm2 are more prone to tumor development than mice without Mdm2 and p53, alone. This suggests that p19Arf has Mdm2- and p53-independent effects, as well. Investigating this idea lead to the recent discovery of smARF.
Read more about this topic: ARF Tumor Suppressor
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