2003 Fiscal Year Annual Research Report

動物モデルを用いたHTLV-1発がん機構の解析

Research Project

Project/Area Number	15023202
Research Institution	Hokkaido University
Principal Investigator	吉木敬北海道大学, 大学院・医学研究科, 教授 (60220612)
Co-Investigator(Kenkyū-buntansha)	石津明洋北海道大学, 大学院・医学研究科, 講師 (60321957) 池田仁北海道大学, 大学院・医学研究科, 助教授 (20232192) 志田壽利北海道大学, 遺伝子病制御研究所, 教授 (00144395) 外丸詩野北海道大学, 大学院・医学研究科, 助手 (20360901)
Keywords	HTLV-I / 上皮型胸腺腫 / 悪性化 / p16 / ARF / 動物モデル / crm1 / 遺伝子導入ラット
Research Abstract	lckプロモーターの制御下にヒトT細胞白血病ウイルスI型(HTLV-I)のpX遺伝子を発現するlck-pXラットは上皮型胸腺腫を発症する。このラットの腎被膜下に腫瘍化前のlck-pXラット胸腺を移植することにより、胸腺腫の悪性化と考えられる現象が観察された。この悪性胸腺腫では、オリジナルの胸腺腫で認められるp16とARFの発現が認められず、p16/ARF領域遺伝子の欠失が本腫瘍の悪性化に中心的な役割を果たしていると考えられた。HTLV-Iが原因となる成人T細胞白血病(ATL)は一般にキャリア状態から腫瘍化し、くすぶり型や慢性型といった低悪性度のATLから急性型やリンパ腫型といった高悪性度のATLへと進展する経過をたどる。高悪性度のATLへの移行の際にはp16やp53の遺伝子異常を高率に伴っていることが知られている。従って、lck-pXラットでの胸腺腫の悪性化はヒトATLの急性転化でみられる現象の一部を観察している可能性がある。良性腫瘍の状態から高悪性度腫瘍の状態までを連続的に観察できる本実験系はHTLV-I関連腫瘍の悪性化機構を解明する上で有用なin vivoモデルである。一方、HTLV-Iがヒト以外の動物で効率よく増殖できないのは、ウイルス粒子の形成に必要なRexの働きを支持する宿主因子CRM1が、ヒト以外の動物ではHTLV-Iに対して低い支持活性しか示さないためであると考えられている。実際にHTLVV-1持続感染ラットT細胞株にヒトcrm1遺伝子を導入することにより、HTLV-I p19発現が増加した。ヒトcrm1遺伝子導入ラットはHTLV-1に対する高感染感受性宿主となる可能性が期待される。

Research Products

(18 results)

All Other

All Publications (18 results)

[Publications] Tomaru U, et al.: "Detection of virus-specific T cells and CD8+ T-cell epitopes by acquisition of peptide-HLA-GFP complexes : analysis of T-cell phenotype and function in chronic viral infections."Nat.Med.. 9・4. 469-476 (2003)
[Publications] Hakata Y, et al.: "A multifunctional domain in human CRM1 (exportin 1) mediates RanBP3 binding and multimerization of human T-cell leukemia virus type 1 Rex protein."Mol.Cell Biol.. 23・23. 8751-8761 (2003)
[Publications] Zhang X, et al.: "Cellular requirements for CRM1 import and export."J.Biochem. (Tokyo). 134・5. 759-764 (2003)
[Publications] Tomaru U, et al.: "Provirus expansion and deregulation of apoptosis-related genes in the spinal cord of a rat model for human T-lymphocyte virus type I-associated myeloneuropathy."J.Neurovirol.. 9・5. 530-538 (2003)
[Publications] Higuchi M, et al.: "Functional alteration of peripheral CD25^+CD4^+ immunoregulatory T cells in a transgenic rat model of autoimmune diseases."J.Autoimmun.. 20・1. 43-49 (2003)
[Publications] Ishizu A, et al.: "Transduction of dominant negative ATF-1 suppresses the pX gene expression in joint fibroblastic cells derived from HTLV-I transgenic rats."Exp.Mol.Pathol.. 74・3. 309-313 (2003)
[Publications] Tanaka S, et al.: "Tissue specific high level expression of a full length human endogenous retrovirus genome transgene, HERV-R, under control of its own promoter in rats."Transgenic Res.. 12・3. 319-328 (2003)
[Publications] Yang L, et al.: "Epstein-Barr virus infection of rat lymphocytes expressing human CD21 results in restricted latent viral gene expression and not in immunoblastic transformation."J.Med.Virol.. 70・1. 126-130 (2003)
[Publications] Kawada M, et al.: "Vaccination of fusion cells of rat dendritic and carcinoma cells prevents tumor growth in vivo."Int.J.Cancer. 105・4. 520-526 (2003)
[Publications] Nakaya H, et al.: "In vitro model of suicide gene therapy for alpha-fetoprotein-producing gastric cancer."Anticancer Res.. 23・5A. 3795-3800 (2003)
[Publications] Yano T, et al.: "Further evidence of hepatic transdifferentiation in hepatoid adenocarcinomas of the stomach : quantitative analysis of mRNA for albumin and hepatocyte nuclear factor-4α."Pathology. 35・1. 75-78 (2003)
[Publications] Yasuda J, et al.: "Nedd4 regulates egress of Ebora virus-like particles from host cells."J.Virol.. 77・18. 9987-9992 (2003)
[Publications] Cohen CJ, et al.: "Direct phenotypic analysis of human MHC class I antigen presentation : visualization, quantitation, and in situ detection of human viral epitopes using peptide-specific, MHC-restricted human recombinant antibodies."J.Immunol.. 170・8. 4349-4361 (2003)
[Publications] Sakurai A, et al.: "Regulation of human T-cell leukemia virus type-1 (HTLV-1) budding by ubiquitin ligase Nedd4."Microbes Infect.. 6・2. 150-156 (2004)
[Publications] Tsuchikawa T, et al.: "Hematopoietic progenitor cells as possible origins of epithelial thymoma in a human T lymphocyte virus type I pX gene transgenic rat model."Lab.Invest.. 84・2. 245-252 (2004)
[Publications] Yoshiki T.: "Gann Monograph on Cancer Research 50 "Two decades of adult T-cell leukemia and HTLV-I research""Japan Scientific Societies Press. 366 (2003)
[Publications] Shida H, et al.: "Gann Monograph on Cancer Research 50 "Two decades of adult T-cell leukemia and HTLV-I research""Japan Scientific Societies Press. 366 (2003)
[Publications] Yamano Y, et al.: "Gann Monograph on Cancer Research 50 "Two decades of adult T-cell leukemia and HTLV-I research""Japan Scientific Societies Press. 366 (2003)

2003 Fiscal Year Annual Research Report

動物モデルを用いたHTLV-1発がん機構の解析

Principal Investigator

吉木 敬 北海道大学, 大学院・医学研究科, 教授 (60220612)

Research Products

[Publications] Tomaru U, et al.: "Detection of virus-specific T cells and CD8+ T-cell epitopes by acquisition of peptide-HLA-GFP complexes : analysis of T-cell phenotype and function in chronic viral infections."Nat.Med.. 9・4. 469-476 (2003)

[Publications] Hakata Y, et al.: "A multifunctional domain in human CRM1 (exportin 1) mediates RanBP3 binding and multimerization of human T-cell leukemia virus type 1 Rex protein."Mol.Cell Biol.. 23・23. 8751-8761 (2003)

[Publications] Zhang X, et al.: "Cellular requirements for CRM1 import and export."J.Biochem. (Tokyo). 134・5. 759-764 (2003)

[Publications] Tomaru U, et al.: "Provirus expansion and deregulation of apoptosis-related genes in the spinal cord of a rat model for human T-lymphocyte virus type I-associated myeloneuropathy."J.Neurovirol.. 9・5. 530-538 (2003)

[Publications] Higuchi M, et al.: "Functional alteration of peripheral CD25^+CD4^+ immunoregulatory T cells in a transgenic rat model of autoimmune diseases."J.Autoimmun.. 20・1. 43-49 (2003)

[Publications] Ishizu A, et al.: "Transduction of dominant negative ATF-1 suppresses the pX gene expression in joint fibroblastic cells derived from HTLV-I transgenic rats."Exp.Mol.Pathol.. 74・3. 309-313 (2003)

[Publications] Tanaka S, et al.: "Tissue specific high level expression of a full length human endogenous retrovirus genome transgene, HERV-R, under control of its own promoter in rats."Transgenic Res.. 12・3. 319-328 (2003)

[Publications] Yang L, et al.: "Epstein-Barr virus infection of rat lymphocytes expressing human CD21 results in restricted latent viral gene expression and not in immunoblastic transformation."J.Med.Virol.. 70・1. 126-130 (2003)

[Publications] Kawada M, et al.: "Vaccination of fusion cells of rat dendritic and carcinoma cells prevents tumor growth in vivo."Int.J.Cancer. 105・4. 520-526 (2003)

[Publications] Nakaya H, et al.: "In vitro model of suicide gene therapy for alpha-fetoprotein-producing gastric cancer."Anticancer Res.. 23・5A. 3795-3800 (2003)

[Publications] Yano T, et al.: "Further evidence of hepatic transdifferentiation in hepatoid adenocarcinomas of the stomach : quantitative analysis of mRNA for albumin and hepatocyte nuclear factor-4α."Pathology. 35・1. 75-78 (2003)

[Publications] Yasuda J, et al.: "Nedd4 regulates egress of Ebora virus-like particles from host cells."J.Virol.. 77・18. 9987-9992 (2003)

[Publications] Cohen CJ, et al.: "Direct phenotypic analysis of human MHC class I antigen presentation : visualization, quantitation, and in situ detection of human viral epitopes using peptide-specific, MHC-restricted human recombinant antibodies."J.Immunol.. 170・8. 4349-4361 (2003)

[Publications] Sakurai A, et al.: "Regulation of human T-cell leukemia virus type-1 (HTLV-1) budding by ubiquitin ligase Nedd4."Microbes Infect.. 6・2. 150-156 (2004)

[Publications] Tsuchikawa T, et al.: "Hematopoietic progenitor cells as possible origins of epithelial thymoma in a human T lymphocyte virus type I pX gene transgenic rat model."Lab.Invest.. 84・2. 245-252 (2004)

[Publications] Yoshiki T.: "Gann Monograph on Cancer Research 50 "Two decades of adult T-cell leukemia and HTLV-I research""Japan Scientific Societies Press. 366 (2003)

[Publications] Shida H, et al.: "Gann Monograph on Cancer Research 50 "Two decades of adult T-cell leukemia and HTLV-I research""Japan Scientific Societies Press. 366 (2003)

[Publications] Yamano Y, et al.: "Gann Monograph on Cancer Research 50 "Two decades of adult T-cell leukemia and HTLV-I research""Japan Scientific Societies Press. 366 (2003)

吉木敬北海道大学, 大学院・医学研究科, 教授 (60220612)