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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Virology - A Study Section (VIRA)
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Read-Connole, Elizabeth Lee
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Colorado State University-Fort Collins
Schools of Arts and Sciences
Fort Collins
United States
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