2007 Fiscal Year Final Research Report Summary
ROLE OF TRANSCRIPTION FACTOR C-MAF IN THE HTLV-1 LATENT INFECTION
| Project/Area Number |
18590457
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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 | Kinki University |
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Principal Investigator |
HIESHIMA Kunio Kinki University, SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR (10322570)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIE Osamu Kinki University, SCHOOL OF MEDICINE, PROFESSOR (10166910)
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| Project Period (FY) |
2006 – 2007
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| Keywords | ATL / HTLV-1 / CCR4 / c-Maf / Tax / CCL22 |
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| Research Abstract |
Adult T-cell leukemia (ATL) is a malignancy with poor prognosis, which develops after a lengthy latent period of infection with human T-lymphotropic virus type 1 (HTLV-1). Leukemic cells are thought to be derived from CCR4+CD4+Th2 or regulatory T cells, although HTLV-1 can also infect CD8+T cells. Notably, HTLV-1-infected CD8+ T cells- do not become leukemic in vivo. The key is to identify the difference between HTLV-1-infected CD4+ and HTLV-1-infected CD8+T cells.
We noticed that a Th2-related transcription factor c-Maf might play the following key roles in selecting the CD4+ T cells involved in HTLV-1 leukemogenesis: (1) constitutive expression of c-Maf in fresh ATL cells; (2) inhibitory effect of c-Maf on HTLV-1 Tax-dependent LTR activation; and (3) difference in c-Maf expression in CD4+ and CD8+ T cells, i.e., CD4+ T cells express c-Maf under both resting and activating conditions, while CD8+ T cells express c-Maf only under resting conditions. This implies that c-Maf reduces the expression of virus-related proteins, including Tax that is a potent target of CTLs, via LTR suppression in antigen-stimulated CD4+ T cells but not antigen-stimulated CD8+ T cells. This results in the effective depletion of HTLV-1-infected CD8+ T cells by HTLV-1-specific CTLs.
Following Tax transactivation, HTLV-1-infected cells also express the CCR4 ligand CCL22, chemoattract uninfected CCR4+CD4+ T cells, and transmit viral particles to these cells via cell-to-cell interactions. We found that c-Maf also suppresses the activation of the CCL22 promoter, suggesting that c-Maf expression decreases viral transmission to CCR4+CD4+ T cells by suppressing CCL22 expression.
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[Journal Article] Expression of CCR9 in HTLV-1+T cells and ATL cells expressing Tax.2007
Author(s)
Nagakubo D, Jin Z, Hieshima K, Nakayama T, Shirakawa AK, Tanaka Y, Hasegawa H, Hayashi T, Tsukasaki K, Yamada Y, Yoshie O.
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Journal Title
International Journal of Cancer. 120
Pages: 1591-1597
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Aberrant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia.
Author(s)
Nakayama T, Hieshima K, Arao T, Jin Z, Nagakubo D, Shirakawa AK, Yamada Y, Fujii M, Oiso N, Kawada A, Nishio K, Yoshie O.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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