Molecular analysis of aberrant signal transduction of membrane receptors as a basis for diagnosis and treatment of malignant lymphomas

膜受体异常信号转导的分子分析作为恶性淋巴瘤诊断和治疗的基础

基本信息

批准号：
14370067
负责人：
WATANABE Toshiki
金额：
$ 8.9万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

(1)Hodgkin's lymphoma and anaplastic large cell lymphomas (ALCL) : We demonstrated that the constitutive activation of NF-kB results from "ligand-independent activation" of overexpressed CD30 on the Hodgkin/Reed-Sternberg (H-RS)cells, and that inhibition of CD30 signaling by transduction of a dominat negative decoy CD30 that lacks the cytoplasmic region induced apoptotic cell death of H-RS cells (Horie et al., Oncogene 21,2493,2002). We shoed that cytoplasmic aggregation of TRAF2 and TRAF5 proteins represents constant signaling of CD30 (Horie et al., Am J Pathol 160,1647,2002). We demonstrated that the AP-1 binding sequence located near the microsatellite counteracts the suppressive effects of the microsatellite on the CD30 promoter activity (Watanabe et al., Am J Pathol 163,633,2003). We showed that p80NPM-ALK inhibits ligand-independent signal transduction by overexpressed CD30 in ALCL cells though sequestration of TRAF proteins in the complex of NPM-ALK and wild type NPM (Horie et al., Cancer Cell 5,353,2004).(2)ATL :We demonstrated that GSK-3b-b-catenin-TCF/LEF pathway is a possible downstream target of the constitutively activated PKCbll in ATL cells.Expression profile analysis of ATL cells identified 67 genes as specifically overexpressed ones in ATL cells, 44 in activated T-cells of PBMC of HTLV-1 carriers, 24 in HTLV-1 infected cell lines.We revealed 5'-LTR specific CpG heavy methylation of HTLV-1 provirus in ATL cells and infected T-cells in peripheral blood of symptomatic carriers, which may be one base for latent infection of HTLV-1 (Koiwa et al., J Virol 76,9389,2002).

(1)Hodgkin's lymphoma and anaplastic large cell lymphomas (ALCL) : We demonstrated that the constitutive activation of NF-kB results from "ligand-independent activation" of overexpressed CD30 on the Hodgkin/Reed-Sternberg (H-RS)cells, and that inhibition of CD30 signaling by transduction of a dominat negative decoy CD30 that lacks the cytoplasmic region诱导H-RS细胞的凋亡细胞死亡（Horie等人，癌基因21,2493,2002）。我们说，TRAF2和TRAF5蛋白的细胞质聚集代表CD30的恒定信号传导（Horie等，Am J Pathol 160,1647,2002）。我们证明，位于微卫星附近的AP-1结合序列抵消了微卫星对CD30启动子活性的抑制作用（Watanabe等人，AM J Pathol 163,633,2003）。我们表明，p80NPM-Alk抑制了ALCL细胞中CD30过表达的CD30的非配体信号转导，但NPM-Alk-all-all型和野生型NPM中TRAF蛋白的固相抑制了（Horie等人，癌细胞5,353,2004）。 constitutively activated PKCbll in ATL cells.Expression profile analysis of ATL cells identified 67 genes as specifically overexpressed ones in ATL cells, 44 in activated T-cells of PBMC of HTLV-1 carriers, 24 in HTLV-1 infected cell lines.We revealed 5'-LTR specific CpG heavy methylation of HTLV-1 provirus in ATL cells and infected T-cells in peripheral blood有症状的载体，这可能是HTLV-1潜在感染的基础之一（Koiwa等，J Virol 76,9389,2002）。