The human T-cell leukemia virus type-1 (HTLV-1) is a complex retrovirus etiologically linked to an aggressive and generally fatal malignancy called adult T-cell leukemia (ATL). Only a small percentage of infected individuals develop ATL following a prolonged latency period of up to 30 years post infection. The dominant mechanism driving virus transmission in an individual is through clonal expansion of HTLV-infected cells. The HTLV-encoded protein Tax is the dominant player in promoting mitotic replication, and is directly linked to malignant transformation. Tax is a potent transcriptional activator that stimulates HTLV-1 viral gene expression and contributes to deregulation of critical pathways in the infected cell. Three enhancer elements, called viral cyclic AMP response elements (vCREs), are located in the HTLV-1 transcriptional control region and are critical to Tax-activated transcription. Tax associates with the vCREs through protein-DNA interactions and protein-protein interactions with the cellular transcription factor CREB. Together, this complex recruits the cellular coactivators CBP/p300, which is a fundamental step in transcriptional activation of HTLV-1. The role of Ser133-phosphorylated CREB (pCREB) in mediating Tax function in HTLV-1 transcription has been controversial. However, our recent studies reveal that Tax-dependent p300 recruitment and viral transcription is dependent upon CREB phosphorylation. Consistent with this observation, we recently found that Tax stimulates the activity of specific calcium/calmodulin kinases that converge on CREB phosphorylation and induces constitutively elevated levels of pCREB in vivo. In addition to inducing CREB phosphorylation, Tax also binds in a stable complex with pCREB at the cyclin D1 CRE. We propose to biochemically dissect the interconnection between Tax, pCREB, the CaM-kinases and cyclin D1, and investigate the molecular mechanisms of Tax deregulation of these critical cellular proteins. The effects of Tax-induced CREB phosphorylation on HTLV-1 and cyclin D1 transcription represent the major themes of this proposal.
This proposal seeks to better understand the transcriptional activation properties of the Tax protein, encoded by the Human T-cell Leukemia Virus, type 1. The Tax oncoprotein is responsible for malignant transformation by the virus.
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