Kim, Young-Mi, authorNyborg, Jennifer K., advisor2024-03-132024-03-132008https://hdl.handle.net/10217/237819Human 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) and to a chronic inflammatory neurological disease. Only a small percentage of infected individuals develop ATL following a prolonged latency period of up to 30 years post infection. The dominant mechanism of virus transmission in an infected individual is through clonal expansion of HTLV-1 infected cells. The HTLV-1-encoded protein Tax is the prominent player in promoting mitotic replication. Tax is also directly linked to malignant transformation and the etiology of ATL. Tax is a potent transcriptional activator that stimulates HTLV-1 viral gene expression. Three 21 base pair repeat enhancer elements called viral cyclic AMP response elements (vCREs), located in the HTLV-1 transcriptional control region, are critical to Tax-activated transcription. Tax associates with the vCREs through protein-DNA interactions and through protein-protein interaction with the cellular transcription factor cAMP response element binding (CREB) protein. Together this complex recruits the cellular coactivators CBP/p300. The role of Ser133 phosphorylated CREB in mediating Tax function in HTLV-1 transcription has long been controversial. Our data reveal that CREB phosphorylation is absolutely required for viral Tax transactivation. Consistent with this, Tax induces constitutively elevated levels of phosphorylated CREB in vivo and in vitro. We further investigated the mechanism of Tax-mediated CREB phosphorylation and uncovered a novel function of Tax: stimulation of CREB phosphorylation via the Ca2+/Calmodulin (CaM)-dependent protein kinase (CaM kinase) pathway to promote viral transcription. In addition to Tax-dependent CREB phosphorylation, we found that Tax upregulates B-cell lymphatic leukemia protein 3 (Bcl-3) and cyclin D1 expression, two key determinants of cell fate. Furthermore, Tax interacts with Bcl-3 in vivo and in vitro. Deregulation of these key host-cell proteins by Tax may contribute to the transformation of T-cells.born digitaldoctoral dissertationsengCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.Bcl-3CREBcyclin D1HTLVhuman T-cell leukemia virustaxtransformationbiochemistrymedicineoncologyTextPer the terms of a contractual agreement, all use of this item is limited to the non-commercial use of Colorado State University and its authorized users.