Abstract
The Human T-cell Leukemia Virus Type-1 (HTLV-1) is a complex oncogenic deltaretrovirus that infects and transforms CD4+ T-lymphocytes and is the etiological agent of Adult T-cell Leukemia/Lymphoma (ATL). HTLV-1 latency-maintenance factor p30II downregulates proviral gene expression at the transcriptional and posttranscriptional levels and aids in immune escape from the host immune surveillance. HTLV-1 p30II competes with HTLV-1 transactivator Tax for binding to CBP/p300 coactivator; this competition determines if there is Tax-mediated transcription initiation or viral gene silencing induced by p30II. Our research group has previously demonstrated that the HTLV-1 p30II accessory protein induces the p53 tumor suppressor and prevents p53 acetylation on K120 by TIP60, thus promoting survival of HTLV-1-infected cells. p53 is mutated or inactivated in half of human malignanices; importantly, it remains wildtype in ATL. Furthermore, our recent studies have shown that p30II induces the expression of p53-induced pro-survival genes, such as TIGAR (Tp53 induced glycolysis and apoptosis regulator). TIGAR promotes antioxidant function and diminishes accumulation of damaging ROS by upregulating levels of NADPH and reduced glutathione. My studies have demonstrated that the HTLV-1 latency-maintenance factor p30II cooperates with the viral oncoproteins, Tax and HBZ, and protects HTLV-1-infected cells from oncogene-associated oxidative damage in the presence of functional TIGAR. Moreover, this cooperation promotes oncogenic transformation of HTLV-1-positive cells by dampening cytotoxocity through p30II-mediated TIGAR induction and enhancing oncogenic potential of viral oncoproteins. Co-expression of p30II protected cells from Tax/HBZ-associated autophagy, mitophagy, ROS accumulation, mitochondrial depolarization, apoptosis, senescence, genomic and mitochondrial DNA damage in a TIGAR-dependent manner. Moreover, my project was focused on identifying molecular and cellular pathways involved in induction and mitochondrial targeting of TIGAR by HTLV-1 p30II. Determining the exact signaling pathway of TIGAR induction could aid in targeting ATL cells to oxidative damage and cell programmed cell death. Significantly, elevated TIGAR expression has accompanied many human malignancies which frequently correlates with resistance to chemotherapy and high mortality rates. Enhanced levels of TIGAR are observed in highly-penetrant NOD/SCID xenograft mouse model of HTLV-1-induced T-cell lymphoma that was successfully established in my studies. Our in vivo findings suggest that knockdown of TIGAR reduces the tumor burden, promotes higher survival rates, downregulates levels of oncoproteins and metastatic potential of cancer cells. These studies allude to a novel role of TIGAR in protecting ATL cells from cytotoxic damage. Our research suggests that targeting TIGAR could aid in sensitizing chemoresistant ATL lymphocytes to successful anticancer treatment.
In approximately half of all cancers, p53 is either mutated or functionally inactivated. However, in the majority of ATL patient isolates, the wildtype p53 protein continues to be expressed at high levels. My studies have shown that p30II not only cooperates with c-Myc, but also activates p53 and induces the expression of p53-dependent pro-survival genes, such as TIGAR (Tp53 induced glycolysis and apoptosis regulator). Through the induction of p53 and TIGAR, p30II may allow for the continued proliferation of HTLV-1 transformed cells and conceivably aid in disease progression. These studies not only provide a plausible mechanism for p30II-mediated cell survival, but also allude to a novel pro-oncogenic facet to the guardian of the genome, p53.
Degree Date
Spring 5-16-2020
Document Type
Thesis
Degree Name
Ph.D.
Department
Biological Science
Advisor
Robert Harrod
Second Advisor
Richard Jones
Third Advisor
Steven Vik
Fourth Advisor
Brian Zoltowski
Number of Pages
242
Format
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Recommended Citation
Bowley, Tetiana, "Determining how the Human T-cell Leukemia Virus Type-1 (HTLV-1) Latency-Maintenance Factor p30ll Modulates Antioxidant- Signaling to Promote Oncogene Activation during Retroviral Carcinogenesis" (2020). Biological Sciences Theses and Dissertations. 8.
https://scholar.smu.edu/hum_sci_biologicalsciences_etds/8