Project Details


The human DNA tumor virus adenovirus encodes two transforming genes, E1A
and E1B, which cooperate to transform primary rodent cells. The E1A gene
products efficiently stimulate cell proliferation but fail to transform
cells due to the induction of programmed cell death (apoptosis).
Induction of apoptosis by E1A is mediated by the product of the p53 tumor
suppressor gene indicating that p53 can function as a tumor suppressor
by initiating cell death. Expression of the E1B gene or the human bcl-2
proto-oncogene, blocks E1A-induced p53-dependent apoptosis to produce
transformation. Thus, deregulation of cell growth control must be coupled
to suppression of an intrinsic cell suicide response for the efficient
transformation of primary cells. The E1B gene encodes two unique l9kDa
and 55kDa proteins, both of which block apoptosis by interfering with the
function of p53. The E1B 55K protein binds to and inactivates p53
directly, whereas the.mechanism utilized by the E1B l9K protein to
inhibit p53-mediated apoptosis is not yet known. Overexpression of the
human Bcl-2 protein will similarly block p53-dependent apoptosis and will
substitute for the E1B l9K protein in all functional assays. It is highly
probable that the E1B l9K protein represents the viral equivalent of Bcl-
2. I intend to determine how the E1B l9K and Bcl-2 proteins act at the
biochemical level to block p53-dependent apoptosis. An essential aspect
of this work is to identify the cellular proteins with which the E1B l9K
and Bcl-2 proteins interact. We have evidence that the E1B l9K protein
does not bind p53 directly, indicating that the l9K protein is an
indirect modifier of p53 function. First, the cellular proteins which
interact with the E1B l9K protein will be identified. Second, I will
determine how the interaction prevents the apoptotic activity of p53. The
two-hybrid system in yeast will be utilized to identify cellular proteins
which interact with the E1B l9K protein. This work will complement the
ongoing NIH funded project to identify l9K binding proteins by strictly
biochemical means. The goal of these aims is to develop a complete
mechanism by which the cell controls the activity of p53. It is becoming
increasingly apparent the regulation of death may be as important as
regulation of proliferation, as an intracellular defense against viral
infection and cancer. Determining how apoptosis is induced by p53 and how
the transforming proteins of DNA tumor viruses intervene and subvert this
process is of fundamental importance to understanding the cause and
prevention of cancer.
Effective start/end date1/1/9512/31/00


  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute


  • Cancer Research
  • Cell Biology


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.