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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）霍奇金淋巴瘤和间变性大细胞淋巴瘤（ALCL）：我们证明了NF-kB的组成性激活是由霍奇金/里德-斯滕伯格（H-RS）细胞上过表达的CD30的"配体非依赖性激活"引起的，并且通过转导缺乏胞质区域的显性负性诱饵CD30来抑制CD30信号传导诱导H-RS细胞的凋亡性细胞死亡（Horie et al.，Oncogene 21，2493，2002）。我们发现TRAF2和TRAF5蛋白质的细胞质聚集代表了CD30的恒定信号传导（Horie et al.，Am J Pathol 160，1647，2002）。我们证明了位于微卫星附近的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，p80 NPM-ALK通过在NPM-ALK和野生型NPM的复合物中螯合TRAF蛋白来抑制ALCL细胞中过表达的CD30的配体非依赖性信号转导（Horie等人，Cancer Cell 5，353，2004）。（2）ATL：我们证明GSK-3b-b-catenin-TCF/LEF通路是ATL细胞中组成性激活的PKCbl 1的可能下游靶点。ATL细胞的表达谱分析鉴定了67个基因在ATL细胞中特异性过表达，44个在HTLV-1携带者的PBMC的活化T细胞中，24个在HTLV-1感染的细胞系中。我们揭示了在ATL细胞和有症状的携带者的外周血中的感染T细胞中的HTLV-1前病毒的5 '-LTR特异性CpG重甲基化，这可能是HTLV-1潜伏感染的基础之一（Koiwa et al.，J Virol 76，9389，2002）。