2006 Fiscal Year Final Research Report Summary
Analysis of HIV Tat protein-mediated Kaposi's sarcoma development mechanism
| Project/Area Number |
17590423
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Virology
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| Research Institution | Kagoshima University (2006)
St. Marianna University School of Medicine (2005) |
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Principal Investigator |
KUSANO Shuichi Kagoshima University, Graduate School of Medical and Dental Sciences, Associate Professor, 大学院医歯学総合研究科, 助教授 (10350662)
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| Project Period (FY) |
2005 – 2006
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| Keywords | KSHV / HIV / I-mfa-domain protein / Wnt signal / signal transduction / HHV-8 |
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| Research Abstract |
The latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is expressed in all KSHV-associated malignancies. LANA is an essential protein for replication and maintenance of the viral episomes during latent infection. In addition, LANA is also known to interact with glycogen synthase kinase (GSK)-3 β and repress GSK-3 β-mediated degradation of β-catenin by affecting intracellular distribution of GSK-3 β. Since stabilization of 3-catenin has been described in a variety of human cancers, it is suggested that the modulation of GSK-3 β by LANA may be a contributing factor in KSHV-associated malignancies. The human I-mfa domain-containing protein (HIC) has been identified as a negative modulator of HIV-1 Tat-mediated transcription from HIV-1 L TR. HIC contains a cysteine-rich C-terminal domain with a high degree of homology to the C-terminal domain of I-mfa, termed an I-mfa domain, and the regulatory properties of HIC depend on this C-terminal domain. The
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I-mfa domain is also required for I-mfa inhibition of myogenic basic helix-loop-helix proteins by preventing nuclear locali zation and DNA binding. In addition, our recent study has shown that HIC and I-mfa interact with GSK-3 β-binding region of Axin and repress its regulations of Wnt and JNK pathways. In this study, we show that both I-mfa domain proteins, HIC and I-mfa, interacted with LANA in vivo throught their I-mfa domains. The N-terminal 275 amino acid region of LANA that contains interaction and phosphorylation sites of GSK-3 β was required for this interaction. Reporter analysis using T-cell factor-specific binding-site revealed that HIC and GSK-3 β synergistically inhibited LANA-mediated stimulation of Wnt signaling pathway. In addition, HIC suppressed synergistic simulation of Wnt signaling in the presence of HIV Tat and KSHV LANA. These observations indicate that I-mfa domain proteins may affect the LANA-mediate regulation of GSK-3 β and contribute to inhibition of tumor development in KSHV-infected cells. Less
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