Human T cell lymphotrophic virus type I (HTLV-I) is the etiologic agent of two diseases: HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukemia (ATL). The 3' end of the virus encodes a 353 amino acid, 40 kiloDalton, phosphoprotein known as Tax. Tax activates the transcription of viral and host genes somehow by modulating the activity of transcription factors which recognize the CREB, NF-kappaB, and SRF promoter elements. In each case, Tax not only interacts with the transcription factor-DNA complex but also with associated factors. For example, Tax interacts with both CREB and the coactivator CBP, resulting in viral gene expression. There is strong evidence that Tax plays a critical role in viral oncogenesis in ATL patients. ATL is rapidly aggressive and chemotherapy-resistant T cell cancer, ultimately resulting in the patient's death within an average of 6 months. An estimated 10-20 million people in the world are infected with HTLV-I, and transmission primarily occurs through human breast milk and to a lesser extent, blood transfusions, IV drug use, and sexual contact. Once the patient is diagnosed with ATL, the survival probability of the patient is extremely small since there is no known cure for the cancer. Laboratory studies have shown that Tax induces the immortalization of primary cells and causes the formation of soft agar colonies and tumors in nude mice. The goal of the proposal is to determine the mechanism(s) of Tax activation of the SRF transcription pathway. Published data indicates that the Tax-CREB interactions are important for viral gene expression and that the Tax-NF-kappaB interactions are important for maintenance of the transformed phenotype. We hypothesize that the Tax-SRF interactions are essential for initiation of the transformed phenotype. To understand the role of Tax in the SRF pathway, we will determine the mechanism of Tax activation of the serum response element (SRE). Tax activation of promoters containing an SRE must require that the positive regulators are active and negative regulators are inactive, and the events must occur constitutively. Our approach will be to examine the effects of Tax on three aspects of SRF function: assembly of the basic transcription complex on the promoter, activity of the MAPK pathway (positive regulator), and activity of the inhibitor Id (negative regulator).
| Shuh, Maureen; Beilke, Mark (2005) The human T-cell leukemia virus type 1 (HTLV-1): new insights into the clinical aspects and molecular pathogenesis of adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-associated myelopathy (TSP/HAM). Microsc Res Tech 68:176-96 |
