Dr Turnell

We are particularly interested in dissecting the relationship between E1A and the ubiquitin/proteasome pathway. We have shown that the N-terminal region and conserved region 2 (CR2) of E1A can enhance p53 stability through direct interaction 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. Our results suggest that APC/C-CBP/p300 function may be targeted directly by E1A during cellular transformation. Moreover, we have also determined a role for CBP in regulating APC/C function in mitosis.

We are now trying to dissect further the complex relationship between E1A and the ubiquitin/proteasome pathway.

• Rasti M, et al (2006) Roles for APIS and the 20S proteasome in adenovirus E1A-dependent transcription. EMBO J (in press).
• Turnell AS, et al (2005) The APC/C and CBP/p300 cooperate to regulate transcription and cell-cycle progression. Nature 438: 690-5.
• Zhang X, et al (2004) The targeting of the proteasomal regulatory subunit S2 by adenovirus E1A causes inhibition of proteasomal activity and increased p53 expression J Biol Chem. 279: 25122-33.
• Turnell AS, et al (2000) Regulation of the 26S proteasome by adenovirus E1A. EMBO J 19:4759-73.