The Proto-Oncogene Bcl3, Induced by Tax, Represses Tax-Mediated Transcription via p300 Displacement from the Human T-Cell Leukemia Virus Type 1 Promoter

Abstract

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 Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus etiologically linked to an unusually aggressive and ultimately fatal malignancy called adult T-cell leukemia. Adult T-cell leukemia is characterized by the presence of a chromosomally integrated HTLV-1 provirus in highly aneuploid T cells (33). However, the majority of HTLV-1-infected individuals remain lifelong asymptomatic carriers despite the fact that up to 70% of their CD4 ϩ T cells carry integrated provirus (3, 4). The molecular events that lead to HTLV-1-dependent transformation of the infected T cell remain enigmatic.HTLV-1 encodes a number of nonstructural proteins that participate in the life cycle of the virus. These include p12, p13, p30, HBZ, Rex, and Tax (for a review, see reference 34). Of these regulatory proteins, the oncoprotein Tax has been well characterized as a critical player in both viral and cellular transcription, as well as malignant transformation. Tax is a strong transcriptional activator required for efficient expression of the viral genome. Tax activates HTLV-1 transcription through three conserved cyclic AMP response elements (CREs) located in the transcriptional control region of the virus. These elements, called viral CREs (vCREs) serve as the binding site for a complex composed of Tax and the cellular transcription factor CREB (25,29,32). Together, the Tax/ CREB complex recruits the cellular coactivators CBP/p300 via direct interaction with their conserved KIX domain (14, 28).Phosphorylation of CREB at serine 133 (pCREB) is essential for strong p300 recruitment by the promoter-bound Tax/CREB complex. As such, pCREB is required for transcriptional activation by Tax (14). Consistent with these observations, Tax has been found to promote CREB phosphorylation in the infected cell, purportedly to ensure sufficient pCREB availability for Tax activation of viral gene expression (24,55,56).Mitotic replication has been established as a major vehicle of viral transmission within an infected individual. The Tax protein is required for the promotion of clonal proliferation and is directly linked to malignant transformation (1). Tax triggers changes in a variety of intracellular signal transduction pathways and deregulates gene expression though interaction with many different cellular proteins (17). For example, Tax-mediated activation of the NF-B pathway results in the upregulation of a large num...

Knockdown of Bcl-3 Inhibits Cell Growth and Induces DNA Damage in HTLV-1-infected Cells)

“…Tax protein is directly responsible for the transcription of Bcl-3 (Kim et al, 2008) and a post-transcriptional mechanisms associated with PI3K-Akt pathway is also involved in the accumulation of Bcl-3 protein (Saito et al, 2010). In this study, we first confirmed the elevated mRNA and protein levels of Bcl-3 in HTLV-1 positive cell lines.…”

“…Expression of Tax is also responsible for the persistent NF-κB activation and NF-κB p65 nuclear translocation. Kim et al have indicated that Tax induces Bcl-3 expression primarily through activation of NF-κB pathway (Kim et al, 2008). In the present study, p65 nuclear translocation was observed in TaxP cells which continuously express Tax protein.…”

“…Previous studies have correlated HTLV-1 infection and elevated Bcl-3 expression (Hishiki et al, 2007;Saito et al, 2010). High level of Bcl-3 was detected in many HTLV-1-infected cell lines and ATL cells, and could be transcriptionally activated by Tax protein and HTLV-1 infection (Kim et al, 2008). However, the roles of elevated Bcl-3 in HTLV-1-infected and Tax positive cells have not been fully discovered.…”

NF-κB, the first quarter-century: remarkable progress and outstanding questions

“…Finally, BCL-3 may also be a cofactor for other transctiption factors. BCL-3 binds TORC3 (transducer of regulated CREB activity 3) and Tax/pCREB complexes and represses transcription by preventing p300 recruitment to the HTLV promoter (Hishiki et al 2007;YM Kim et al 2008). A recent report identified ERRa and PPARa as BCL-3-binding partners (Yang et al 2009).…”

Do miRNAs Hold the Key to Controlling EBV-driven Tumorigenesis?

“…Some viruses such as HCV may promote carcinogenesis indirectly, but many act as direct carcinogens by expressing at least one viral oncogene that can promote or maintain the malignant phenotype. However, human T-lymphotropic virus-1 is present in adult T-cell leukemia/lymphoma [4], but expression of its putative oncogene v-tax is frequently absent in the malignant cells [5], which suggests that other mechanisms are also involved. Nevertheless, it appears that viral-associated malignancies may be biological accidents, resulting from survival mechanisms employed to prevent destruction in their host cells.…”