Project Details
Description
The E1A oncogene of the DNA tumor virus adenovirus stimulates cell
proliferation by inhibiting the actions of negative cell cycle regulators
such as the Rb tumor suppressor protein. The p53 tumor suppressor protein
responds to this growth deregulation with the induction of programmed cell
death (apoptosis). Thus, p53 acts as a defense against viral infection and
transformation through activation of apoptosis. The E1B oncogene of
adenovirus cooperates with E1A in transformation and sustains viral
infection by inhibiting E1A-induced, p53-dependent apoptosis. E1B possesses
two independent mechanisms for disabling p53 function encoded by the l9K
and 55K proteins. The 55K protein binds to and inhibits p53 directly,
whereas the 19K protein is a member of the Bc1-2 family of apoptosis
inhibitors. E1B 19K expression can block apoptosis induced not only by E1A
and p53, but also by tumor necrosis factor, and Fas antigen, suggesting
that it acts at a point central to the regulation of apoptosis by multiple
pathways. We intend to establish the molecular basis for the regulation of
apoptosis by the 19K protein through the characterization of 19K-
interacting cellular proteins. The 19K protein associates with several
proteins of either known or potential importance in the regulation of
apoptosis. One 12K protein requires identification, whereas two others are
known: the nuclear envelope structural protein lamin A and the Bc1-2
associated protein and antagonist Bax. The identity of the 12K protein will
be determined as will its role in apoptosis. Lamins are required for
nuclear assembly and organization and lamin destruction is an early event
during apoptosis. We will investigate the role of lamins in the modulation
of the nuclear events of apoptosis (chromatin condensation and DNA
fragmentation) and how the association between 19K and lamins may maintain
lamin functional integrity. The association between 19K and Bax suggests
that 19K functions similarly to Bc1-2 through the interaction with the
death promoter. The functional consequences of the interaction between 19K
and Bax will be determined. By studying the interaction of the 19K protein
with these cellular proteins we hope to understand how cell suicide
instigated by growth deregulation is regulated. Defining the process of
apoptosis at the molecular level is of basic importance to understanding
development, cancer, degenerative diseases, and viral pathogenesis.
Status | Finished |
---|---|
Effective start/end date | 1/1/92 → 6/30/01 |
Funding
- National Cancer Institute: $194,853.00
ASJC
- Cell Biology
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