Adenovirus gene regulation of tumour suppressors

Research in our laboratory is concerned principally with determining how the transforming genes of adenovirus, E1A and E1B, regulate tumour suppressor gene products such as p53 and pRb, to promote cellular transformation and viral replication. In this regard we are particularly interested in dissecting the relationship between E1A and the ubiquitin/proteasome pathway. To this end, we have shown that the N-terminal region and conserved region 2 (CR2) of E1A can enhance p53 stability through direct association with 19S proteasomal ATPases S4 and S8, and 19S proteasomal non-ATPase S2 subunits, respectively. More recently we have also determined that CR3 of E1A also binds the 19S proteasomal S8 subunit and 20S proteasomes to regulate early viral transcription.

We have also determined that the N-terminal region, and CR1, of E1A share significant functional homology with components of the E3 ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C). Specifically, through protein–protein interaction domains that are evolutionarily conserved in adenovirus E1A, APC/C subunits APC5 and APC7 interact directly with the transcriptional coactivators CBP and p300 to stimulate intrinsic CBP/p300 acetyltransferase activity and potentiate CBP/p300-dependent transcription. Interestingly, APC5 and APC7 also suppress E1A-mediated cellular transformation in a CBP/p300-dependent manner, suggesting that APC/C-CBP/p300 function may be targeted directly by E1A during cellular transformation. In addition to these findings, we have also determined a role for CBP in regulating APC/C function in mitosis.

Future studies in our laboratory will attempt to further dissect the complex relationship between E1A and the ubiquitin/proteasome pathway.

Publications

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