The proto-oncogene Bcl3, induced by Tax, represses Tax-mediated transcription via p300 displacement from the human T-cell leukemia virus type 1 promoter.

The etiology of human T-cell leukemia virus type 1 (HTLV-1)-induced adult T-cell leukemia is linked to the expression of the viral oncoprotein Tax. Although the mechanism of retroviral transformation is unknown, Tax interferes with fundamental cellular processes, including proliferation and apoptosis, and these events may directly link Tax to early steps in malignant progression. In this study, we examined the interplay between Tax and the potent proto-oncogene B-cell chronic leukemia protein 3 (Bcl3). Bcl3 is a critical regulator of cell survival and proliferation and is overexpressed in HTLV-1-infected cells. We found that Tax induced Bcl3 expression through stimulation of the NF-kappaB pathway. An intronic NF-kappaB binding site within the Bcl3 gene served as the primary target of Tax-induced NF-kappaB activation. We next considered the consequence of Bcl3 overexpression on Tax function. Interestingly, we found that Bcl3 formed a stable complex with Tax and that this complex potently inhibited Tax-dependent HTLV-1 transcription. Importantly, Bcl3 associated with the HTLV-1 promoter in a Tax-dependent manner and inhibited the binding of the critical cellular coactivator p300. The conserved ankyrin repeat domain of Bcl3 mediated both Tax binding and inhibition of p300 recruitment to the HTLV-1 promoter. Together, these data suggest that Tax-induced Bcl3 overexpression benefits the virus in two important ways. First, Bcl3 may promote cell division and thus clonal proliferation of the virus. Second, Bcl3 may attenuate virion production, facilitating immune evasion. One consequence of this regulatory loop may be Bcl3-induced malignant transformation of the host cell.