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.
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.
| Romeo, Megan M; Ko, Bookyung; Kim, Janice et al. (2015) Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30(II) accessory protein and the induction of oncogenic cellular transformation by p30(II)/c-MYC. Virology 476:271-88 |
| Harrod, Robert (2011) Inhibiting HDACs in a preclinical model of HTLV-1-induced adult T-cell lymphoma. Leuk Res 35:1436-7 |
