This project is to understand the processes used by the human T cell leukemia virus type 1 (HTLV-1)for the transformation of human cells. There are several concepts on how a cell can progress from normal physiology to achieve a transformed phenotype. To characterize transformation, we have studied cellular genetic integrity, cell cycle progression and the checkpoints within a cell that guard normal cellular division. We have studied several cellular proteins and cellular microRNAs whose functions are perturbed by infection with a transforming virus. In the 2010 - 2011 period, we have made the following scientifc findings as outlined below. We have studied oncogenic microRNAs and have discovered inhibitors of these RNAs that reverse transformation. We screened a small chemical library and identified compounds that suppress microRNA activity. Two compounds were characterized;one impaired Dicer activity while the other blocked small RNA-loading into an Argonaute 2 (AGO2) complex. We developed a cell-based model of miRNA-dependent tumorigenesis, and using this model, we observed that treatment of cells with either of the two compounds effectively neutralized tumor growth. We have identified a microRNA that silences the tumor suppressor DLC-1 and promotes HCV replication in cells. Aberrant expression of miRNA has been linked to a variety of cancers, including hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) infection is considered a major cause of chronic liver disease and HCC, although the mechanism of virus infection-associated hepatocarcinogenesis remains unclear. We report a direct role of miR-141 induced in HCV-infected primary human hepatocytes that target the tumor suppressor gene DLC-1 (a Rho GTPase-activating protein), which is frequently deleted in HCC, and other solid human tumors. We present several lines of evidence that efficient HCV replication requires miR-141-mediated suppression of DLC-1. Our collective results suggest a novel mechanism of HCV infection-associated miRNA-mediated regulation of a tumor suppressor protein that has the ability to influence cell proliferation and transformation. NF-kB is important for HTLV-1 mediated transformation of cells. The HTLV-1 viral oncoprotein Tax functions pivotally in leukemogenesis through its potent activation of NF-B. Recent findings suggest that protein ubiquitination is crucial for proper regulation of NF-B signaling and for Tax activity. We have identified a novel ubiquitin-specific peptidase USP20 which deubiquitinates TRAF6 and Tax and suppresses interleukin 1 (IL-1)- and Tax-induced NF-B activation. Our results point to USP20 as a key negative regulator of Tax-induced NF-B signaling that could serve to attenuate HTLV-1 transformation of cells.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2011
Total Cost
$907,824
Indirect Cost
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State
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Tang, Sai-Wen; Chen, Chia-Yen; Klase, Zachary et al. (2013) The cellular autophagy pathway modulates human T-cell leukemia virus type 1 replication. J Virol 87:1699-707
Zhang, Quan; Jeang, Kuan-Teh (2013) Long non-coding RNAs (lncRNAs) and viral infections. Biomed Pharmacother 3:34-42
Klase, Zachary; Jeang, Kuan-Teh (2013) Reciprocal functional pseudotyping of HIV-1 and HTLV-1 viral genomes by the heterologous counterpart envelope proteins. Virology 443:106-12
Zane, Linda; Yasunaga, Junichiro; Mitagami, Yu et al. (2012) Wip1 and p53 contribute to HTLV-1 Tax-induced tumorigenesis. Retrovirology 9:114
Chen, Chia-Yen; Chi, Ya-Hui; Mutalif, Rafidah Abdul et al. (2012) Accumulation of the inner nuclear envelope protein Sun1 is pathogenic in progeric and dystrophic laminopathies. Cell 149:565-77
Chi, Ya-Hui; Chen, Chia-Yen; Jeang, Kuan-Teh (2012) Reversal of laminopathies: the curious case of SUN1. Nucleus 3:418-21
Majone, Franca; Jeang, Kuan-Teh (2012) Unstabilized DNA breaks in HTLV-1 Tax expressing cells correlate with functional targeting of Ku80, not PKcs, XRCC4, or H2AX. Cell Biosci 2:15
Zane, Linda; Jeang, Kuan-Teh (2012) The importance of ubiquitination and sumoylation on the transforming activity of HTLV Tax-1 and Tax-2. Retrovirology 9:103
Jeang, Kuan-Teh (2011) Human T-cell leukemia virus type 1 (HTLV-1) latency: death signaling awakens the sleeping retrovirus. Cell Cycle 10:3824-5
Yasunaga, Junichiro; Lin, Frank C; Lu, Xiongbin et al. (2011) Ubiquitin-specific peptidase 20 targets TRAF6 and human T cell leukemia virus type 1 tax to negatively regulate NF-kappaB signaling. J Virol 85:6212-9

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