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.