Study On The Relationship Between Tumor Suppressor Protein ARF And Adenovirus Protein E1A

The ARF tumor suppressor is one of the most important oncogenic stress sensors. ARF exerts'"oncogenic checkpoint" function through both p53-dependent and p53-independent mechanisms. Adenovirus El A targets cellular Rb family proteins and P300/CBP to drive early viral transcription and induce cell cycle progression.In this study, we demonstrate a novel p53-independent interaction between p14ARF and adenovirus oncoprotein El A. P14ARF inhibits El A transcriptional function and promotes ubiquitination-dependent degradation of El A. P14ARF over-expression relocalizes El A into nucleolus and inhibits ElA-induced cellular DNA replication independent of p53. Knockdown of endogenous p14ARF increase ElA transactivation. In addition. ElA can competitively inhibit ARF-mdm2 complex formation. These results identify a novel binding partner of p14ARF and reveal a mutually inhibitory interaction between p14ARF and El A. We speculate that ARF-ElA interaction may represent an additional host defense mechanism to limit viral replication. Alternatively, the interaction may allow adenovius to sense the functional state of p53 in host cells, and fine-tune its own replication activity to prevent triggering a detrimental host response.