Roger Grand - Overview
Adenoviruses have been used as a model system in
the study of human cancers for the past forty years. Certain adenovirus
serotypes can cause tumours in newborn rodents whilst transfection of
adenovirus DNA into mammalian cells gives rise to transformed cell lines.
It is now well established that expression of adenovirus early region
1A (AdE1A) is essential for both tumourigenesis and cellular transformation.
Although AdE1A in isolation can transform rodent cells the frequency of
transformation is markedly increased in the presence of a co-operating
oncogene such as adenovirus E1B.
AdE1A exerts its effect on the target cell during transfection (and viral
infection) through a series of protein-protein interactions. Importantly
many of these proteins targets/partners have been shown to be mutated
in various human tumours. It is our primary objective to understand the
roles of binding proteins in the normal cell and how their function is
affected by interaction with AdE1A. Amongst the best characterized AdE1A
binding proteins are pRb (retinoblastoma protein), p300/CRP, TBP (Tata
binding protein) and CtBP (C terminal binding protein) – all of which
are involved, directly or indirectly, in transcriptional regulation.
Recently we have identified a new set of AdE1A interacting proteins; these
have been shown to be regulatory components of the 26S proteasome. At
present it is not clear whether AdE1A only affects proteasomal degradative
activity or whether it also regulates the non-proteasomal activities of
the regulatory binding proteins. It is expected that the full implications
of the interaction of AdE1A with proteasomal components will be determined
in the near future.
A further E1A binding protein, CtBP, is being studied in detail. This
important transcriptional co-repressor interacts with a large number of
cellular proteins through a highly conserved motif which is also present
in the viral protein. The role of CtBP is being studied in normal cells
and the implications of AdE1A’s interaction is being examined in both
infected and transformed cells.
The adenovirus research group has, over the past decade, devoted considerable
effort to the study of the three dimensional structure of AdE1A by NMR
spectroscopy. Up to now the structures of synthetic peptides corresponding
to two important regions of AdE1A have been determined but work is continuing
in attempt to solve structures of larger domains.
In addition to work on AdE1A we have carried out a large number of studies
of the larger AdE1B55K protein AdE1A with a view to understanding the
ways in which it is able to increase the frequency of AdE1A-mediated transformation.
This work, focussing on an investigation of the mode of interaction with
p53 and the search for other binding partners, is continuing.
