SOUTHERN METHODIST UNIVERSITY INC
Grant: $218,250 - National Institutes of Health - Jun. 5, 2009
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Award Description: DESCRIPTION (provided by applicant): Many oncogenic viruses interact with cellular oncoproteins to induce cancers in humans. It is of paramount importance to understand the mechanisms by which transforming viruses cooperate with host factors to promote neoplastic disease. For the past two decades, the human T-cell lymphotropic retrovirus type-1 (HTLV-1) has served as an informative model for viral carcinogenesis. HTLV-1 infects and transforms CD4+ T-lymphocytes, associated with the development of Adult T-cell Leukemia/Lymphoma (ATLL), an often fatal hematological malignancy. A conserved sequence, known as pX, within the 3' region of the HTLV-1 genome encodes five regulatory and accessory proteins, including the transactivator, Tax, and p30II (Tax-ORF-II). While Tax is recognized to be the major oncogenic determinant of HTLV-1, the functions of other pX products in T-cell leukemogenesis are not well defined. We have made significant progress in this area and provided the first evidence that the HTLV-1 accessory protein, p30II, cooperates with the c-MYC oncoprotein to deregulate S-phase cell-cycle entry and induce oncogenic cellular transformation. Our preliminary studies demonstrate that p30II enhances c-MYC-dependent transactivation through interactions with the TIP60 acetyltransferase. HTLV-1 p30II induces Lys- acetylation of c-MYC. Further, we demonstrate that acetylation-defective Lys`Arg c-MYC mutants are impaired for oncogenic transformation by HTLV-1 p30II/c-MYC, which suggests that acetylation may be an important determinant of c-MYC oncogenic potential. A mutant HTLV-1 proviral clone, ACH.p30II, defective for p30II production, is impaired for cooperation with c-MYC. The c-MYC oncoprotein is over-expressed in acute/lymphoma-stage ATLL lymphocytes and tumor fibroblasts from pX transgenic mice, suggesting that cooperation between HTLV-1 and c-MYC may promote neoplastic T-cell transformation and/or disease progression. Based upon these findings, we hypothesize that p30II modulates c-MYC oncogenic functions and contributes to HTLV-1-associated leukemogenesis. The following Specific Aims are proposed: (1) to identify the critical amino acid contacts between HTLV-1 p30II/c-MYC/TIP60 required for p30II effects upon c-MYC transactivation, cell-cycle progression, and oncogenic transformation. (2) To determine how p30II-TIP60 interactions affect c-MYC biochemical properties (acetylation, ubiquitinylation, phosphorylation) and protein stability, as well as the role of c-MYC-posttranslational modifications in viral carcinogenesis. (3) To determine how p30II/c-MYC/TIP60 interactions and p30II-induced Lys-acetylation influence c-MYC functions (transactivation, apoptosis/cellular senescence, cell-cycle progression, anchorage- independence) which may promote oncogenic transformation by HTLV-1 p30II/c-MYC. PUBLIC HEALTH RELEVANCE: The proposed research will advance our understanding of how oncogenic viruses promote neoplastic disease in humans through cooperation with cellular oncoproteins. Using HTLV-1 as a model for viral carcinogenesis, we have gained novel insight regarding the molecular bases for modulation of c-MYC functions by transforming viruses. These studies may lead to the development of targeted therapeutic strategies to inhibit c-MYC oncogenic functions in hematological malignancies and solid tumors.
Project Description: Research activities as described in the award description. The goal of this project is to elucidate the molecular mechanism(s) by which the human T-cell leukemia virus type-1 (HTLV-1) p30II accessory protein cooperates with the c-MYC oncoprotein to deregulate cellular gene expression associated with enhanced oncogenic activity. This research will provide invaluable insight regarding cooperative interactions between transforming viruses and cellular oncogenes which may contribute to disease progression for certain viral-induced human cancers.
Jobs Summary: Faculty/Principal Investigator (PI) performing research for the advancement of science and providing oversight and guidance for Student Graduate Research Assistants. Student Graduate Research Assistants performing research while learning research techniques to prepare them to become research leaders of future generations. Student employees are limited to 20 hours or less while carrying a full course load. The PI?s summer salary is supported by ARRA funds. The project provided support for one part-time undergraduate student during the summer and will provide support for three part-time undergraduate student working as undergraduate student researchers. Also, there will be two graduate students working on the project: one Ph.D. graduate student and one M.S. graduate student. The ARRA funds will significantly support their research training in preparation for future careers in the biosciences. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
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