Jones, Christopher; (1993) E1A mediated activation of the adenovirus E4 promoter. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

An important function of adenovirus E1A proteins upon an adenoviral infection of permissive human cells is the transcriptional activation of viral early genes during the first phase of the lytic cycle. To this end E1A targets a number of cellular transcription factors, many of which are sequence specific DNA binding proteins that directly interact with early viral promoters. Studies of the adenovirus E4 promoter have identified a promoter element, the ATF binding site, that is critical for trans-activation by E1A. Several cellular transcription factors interact with ATF binding sites and are therefore potential targets for E1A. There is significant evidence that E4F and a member of the ATF family (ATF-2) can independently function with E1A to activate the E4 promoter. To assess the role of E4F, I have monitored the effects of point mutations in the ATF/E4F binding sites on E4 promoter activity in vivo using a transient expression assay in HeLa cells. I found that whilst the core motif of these sites is the only upstream requirement for activation of the E4 promoter, an adjacent point mutation that eliminates E4F binding (but has no effect on ATF binding) does not affect E4 promoter activity. These findings indicate that ATF binding sites are the sole requirement for trans-activation of the E4 promoter by E1A. I have also found that some point mutations that strongly reduce E4 promoter activity in vivo have no effect on binding of ATE-2 to these sites in vitro. Therefore these results are inconsistent with the suggestion that ATF-2 alone functions with E1A to activate the E4 promoter. Together with the results of previous studies, these results demonstrate that E1A has evolved multiple options for activating transcription of early viral genes.

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