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Dissertation
Over-representation of MEF-2 isoforms in HTLV-1-induced acute ATLL by facilitating the activity of the antisense promoter
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2021
DOI:
https://doi.org/10.17918/00000692
Abstract
HTLV-1 is a complex human retrovirus, an etiologic agent in causing malignant and intractable T-cell neoplasia. About 5% of infected population would progress to a more aggressive form of non-Hodgkin's lymphoma, termed as Adult T-cell leukemia/Lymphoma (ATLL). MEF-2 (Myocyte enhancer factor-2) are a family of genes, whose isoforms 2A-D are involved in distinct functions in various tissues and whose mutations are implicated in various cancers. We performed novel cyto-analytical techniques to quantitate gene transcripts and protein expression patterns of various ATLL cell-lines and acute ATLL patient cohort of North American ATLL, and established MEF-2A and MEF-2C as the predominant isoforms that were highly over expressed in ATLL patients. Knock-down and chemical inhibition of MEF-2A & 2C resulted in the decrease of the viral copy number and down-regulation of the transactivation viral protein TAX and anti-sense transcribing HTLV-b-zip protein (HBZ), which are important for viral pathogenesis. We also observed protein-protein interactions of MEF-2A and MEF-2C with HBZ, along with transcriptional activators such as JunD, SP-1 family and which control the pathogenesis of the virus. We further used chromatin immuno-precipitation assays to establish the role of MEF-2 isoforms, we observed enrichment of MEF-2 isoforms along the 3'LTR of the virus along with other factors which play an important role in the transcriptional activity at 3' LTR promoter region. The presence of scaffolding proteins that are formed by MEF-2/JunD/HBZ that are enriched at the antisense region of the virus, govern the transcription from the antisense promoter region of the HTLV-1 in the absence or loss of 5'LTR activity. In summary, this study exemplifies the role of MEF-2 isoform(s) and their occupancy at the 3'LTR and how they modulate the various transcription factors via the association with the antisense coding viral gene HBZ to induce ATLL.
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Details
- Title
- Over-representation of MEF-2 isoforms in HTLV-1-induced acute ATLL by facilitating the activity of the antisense promoter
- Creators
- Kiran Madugula
- Contributors
- Pooja Jain (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvi, 189 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991015080649604721