The Human T cell Leukemia Virus (HTLV) is the etiologic agent of adult T cell leukemia (ATL), an aggressive and fatal leukemia of CD4+ T lymphocytes, and is also associated with a neurological demyelinating disease called Tropical Spastic Paraparesis (TSP) or HTLV-I Associated Myelopathies (HAM). The oncogenic potential of HTLV-I resides in the viral Tax oncoprotein, a positive regulator of viral and cellular gene transcription. Interestingly, all HTLV-1 infected cells and Jurkat cells transiently transfected with the HTLV-I Tax gene, express constitutively the Interferon Regulatory Factor-4 (IRF-4), a lymphoid-specific member of the IRF family of transcription factors, indicating that Tax may function as an indirect transactivator the IRF-4 gene. The overexpression of IRF-4 in HTLV-1 infected cells may play a role in viral-mediated cellular transformation and thus in adult T cell leukemia. IRF-4 expression studies revealed its presence in B cells, activated T cell, macrophages and T cells infected with HTLV-I or HTLV-II. In attempt to understand the regulation of IRF-4 expression, promoter analyses were undertaken using genomic footprinting and EMSA. These promoter analyses revealed the involvement of the NF-kappaB and NF-AT family members in IRF-4 regulation. Using IRF-4 as bait in a yeast two hybrid screen, a novel interaction between IRF-4 and the FK506 binding protein 52 (FKBP52), a 59kDa member of the immunophilin family with peptidyl-prolyl isomerase activity (PPIase) as well as chaperone-like functions, was characterized. Inhibition of IRF-4 DNA binding activity as well as transcriptional potential was shown to require functional PPIase of this immunophilin. FKBP52 seems to induce a conformational change in IRF-4 by cis-trans prolyl isomerization which interferes with IRF-4 DNA binding and transactivation. These studies suggest the direct involvement of the immunophilin FKBP52 in the regulation of IRF-4 function by a novel post-translational modification.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.38229 |
| Date | January 2001 |
| Creators | Mamane, Yael. |
| Contributors | Hiscott, John (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Microbiology and Immunology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001832594, proquestno: NQ78724, Theses scanned by UMI/ProQuest. |
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