Summary auto-generated
This study investigated the interaction between human papillomavirus (HPV) E6 oncoproteins and the p300/CBP transcriptional coactivator. Using in vitro binding assays, researchers demonstrated that E6 proteins from both high-risk HPV types (HPV-16, HPV-18) and low-risk types (HPV-11) bind to p300, with binding occurring at the CH1, CH2, and CH3 domains. To determine the biological significance of this interaction, the authors used a transformation-defective adenovirus E1a mutant lacking p300-binding capacity. HPV-16 and HPV-18 E6 proteins efficiently complemented this defect in baby rat kidney cell transformation assays, restoring the ability to cooperate with activated ras in focus formation. Critically, an E6 mutant unable to bind p300 failed to provide complementation, while an E6 mutant defective in p53 degradation retained complementation ability. This demonstrates that the E6–p300 interaction, independent of p53 inactivation, is essential for transformation activity. These findings provide direct biological evidence that p300 binding is functionally important for HPV E6-mediated cellular transformation.
Key findings
- Both high-risk (HPV-16, HPV-18) and low-risk (HPV-11) HPV E6 proteins bind p300 at the CH1, CH2, and CH3 domains, though high-risk types bind more efficiently
- HPV E6 proteins can functionally complement a p300-binding-defective adenovirus E1a mutant in cell transformation assays, restoring cooperation with activated ras
- The E6–p300 interaction is required for transformation activity, as E6 mutants unable to bind p300 cannot complement the E1a defect
- E6-mediated complementation is independent of p53 degradation, indicating the p300 interaction serves a distinct transforming function
- The p300-binding activity appears conserved across papillomavirus types, suggesting this interaction is a fundamental requirement for viral pathogenesis
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Abstract
Previous studies have shown that the human papillomavirus type 16 (HPV-16) E6 protein binds to p300/CBP and abrogates its transcriptional co-activator function. However, there is little information on the biological consequences of this interaction and discrepancy as to whether the interaction is high-risk E6 specific or not. We performed a series of studies to compare the interactions of HPV-18 and HPV-11 E6 with p300, and showed that both high- and low- risk E6 proteins bind p300. In addition, using a transformation-deficient mutant of adenovirus E1a, which cannot interact with p300, we demonstrated that HPV-16, HPV-18 and, to a lesser extent, HPV-11 E6, can complement this mutant in cell transformation assays. In contrast, a mutant of HPV-16 E6 which does not bind p300 failed to rescue the E1a mutant. These results suggest that the E6p300 interaction may be important for the ability of HPV E6 to contribute towards cell transformation.