Bcl-3 was originally identified as a protein that is highly expressed in certain B-cell
lymphomas harboring a 14;19 translocation, and more recent evidence indicates that its
expression is characteristic of a large number of human cancers. A member of the IκB family
of NF-κB inhibitors, Bcl-3 interacts with NF-κB dimers containing p50 or p52 and promotes
transcription of a subset of NF-κB dependent genes. However, neither the role of Bcl-3 in
oncogenesis, nor its role in normal physiology, has been clearly defined.
My research has focused on elucidating the function of Bcl-3 in the context of DNA
damage signaling in order to gain insight into its physiological and pathological roles.
Experiments presented here indicate that Bcl-3 is inducible by DNA damage and is required
for the induction of Hdm2 gene expression and the suppression of persistent p53 activity.
Furthermore, constitutive expression of Bcl-3 suppresses DNA damage-induced p53
activation and inhibits p53-induced apoptosis through a mechanism that is at least partly
dependent on the upregulation of Hdm2. The results provide insight into a mechanism
whereby altered expression of Bcl-3 leads to tumorigenic potential. Since Bcl-3 is required
for germinal center formation, these results further indicate that Bcl-3 may play a critical in
the B-cell maturation process by suppressing p53-dependent apoptosis in response to somatic
hypermutation and class switch recombination.
As aberrant expression of Bcl-3 has been found in an increasing number of human
cancers, my second project set out to investigate whether Bcl-3 plays a role in hepatocellular
carcinoma (HCC). The data indicate that nuclear staining of Bcl-3 is present in a high
percentage of primary HCC tumors compared to adjacent normal tissue. Furthermore,
western blot analysis indicates that high Bcl-3 expression correlates positively with
expression of Hdm-2. These data suggest that Bcl-3 may play a causal role in HCC and
indicate that it may be functioning through inhibition of p53.
Collectively, the work described here proposes a novel function for the oncoprotein
Bcl-3 that provides insight into both its normal and oncogenic roles and provides further
evidence for the expanding role of Bcl-3 in human cancer.