Project Details


DESCRIPTION: (Adapted from the investigator's abstract) Apoptosis is an
inducible response to developmental or environmental stimuli that culminates in
cell suicide. While cell death is essential for development and homeostasis,
increased apoptosis leads to embryonic lethality and degenerative disorders. In
contrast, increased survival is conducive to autoimmune diseases and cancer.
The pro-inflammatory cytokine tumor necrosis factor alpha (TNFa) is produced in
immune and inflammatory responses and triggers competing signaling pathways
that determine whether a cell lives or dies. One pathway promotes cell death,
the other leads to activation of the Rel/NF-kB transcription factors and the
inhibition of apoptosis. Experimental evidence indicates that Rel/NF-kB
regulates the expression of genes that confer resistance to death-inducing
signals. The important role of Rel/NF-kB in immune and inflammatory responses
and in leukemia/lymphomagenesis led one to search for the anti-apoptotic genes
that it controls. Dr. Gelinas has recently identified Bfl-1/A1 as a direct
transcriptional target of NF-kB. Bfl-1/A1 is a pro-survival factor in the
Bcl-2-family of apoptosis regulators. Bfl-1 gene expression was dependent on
NF-kB activity and suppressed TNFa-induced under conditions where endogenous
NF-kB activity was inhibited. Bfl-1 promoter analysis revealed a consensus kB
DNA site responsible for its Rel/NF-kB-dependent induction. These findings are
consistent with reports of bfl-1/a1 gene induction by pro-inflammatory
cytokines in endothelial, leukemic and hemopoietic cells, and of its ability to
confer resistance to various death-inducing agents. The preferential expression
of Bfl-1 in hematopoietic cells and tissues suggests that it may be critical
for carrying-out the protective role of Rel/NF-kB in the immune system and
during inflammation. The ability of Bfl-1 to cooperate with Adenovirus E1A to
transform cells and its overexpression in certain cancers also suggest that
Bfl-1 activation may be an important means by which NF-kB functions in
oncogenesis and promotes cell resistance to anti-cancer therapy. This proposal
is an extension of these preliminary studies. Dr. Gelinas will characterize the
anti-apoptotic and oncogenic functions of Bfl-1 and establish its contribution
to the Rel/NF-kB survival pathway. Experiments will define the mechanism by
which Bfl-1 blocks the apoptotic cascade in lymphoid cells (Aim 1), evaluate
its contribution to Rel/NF-kB-mediated cell survival (Aim 2), and assess its
role in malignancy (Aim 3). These studies will help to decipher the mechanisms
that antagonize the cellular apoptotic response and will provide important
information to understand their contribution to oncogenesis and to the
resistance of tumor cells to anti-cancer treatment.
Effective start/end date7/1/003/31/13


  • National Cancer Institute: $58,188.00
  • National Cancer Institute: $242,045.00
  • National Cancer Institute: $242,045.00
  • National Cancer Institute: $242,045.00
  • National Cancer Institute: $247,822.00
  • National Cancer Institute: $183,634.00
  • National Cancer Institute: $242,045.00
  • National Cancer Institute: $247,664.00
  • National Cancer Institute: $264,545.00


  • Analysis
  • Medicine(all)
  • Oncology
  • Cancer Research
  • Immunology


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.