The tumour suppressor ARF (alternative reading frame) is one of the most important oncogenic stress sensors. ARF provides an ‘oncogenic checkpoint’ function through both p53-dependent and p53-independent mechanisms. In the present study, we demonstrate a novel p53-independent interaction between p14ARF and the adenovirus oncoprotein E1A. p14ARF inhibits E1A transcriptional function and promotes ubiquitination-dependent degradation of E1A. p14ARF overexpression relocalizes E1A into the nucleolus and inhibits E1A-induced cellular DNA replication independent of p53. Knockdown of endogenous p14ARF increases E1A transactivation. In addition, E1A can competitively inhibit ARF–Mdm2 (murine double minute 2) complex formation. These results identify a novel binding partner of p14ARF and reveal a mutually inhibitory interaction between p14ARF and E1A. We speculate that the ARF–E1A interaction may represent an additional host defence mechanism to limit viral replication. Alternatively, the interaction may allow adenovirus to sense the functional state of p53 in host cells, and fine-tune its own replication activity to prevent the triggering of a detrimental host response.
Interactive toxicity and stress protein expression by vinylidene chloride and monochloroacetate in precision-cut rat liver slices.
