STRUCTURE FUNCTION STUDY OF A NOVEL TUMOR SUPPRESSOR, EPHA

新型肿瘤抑制因子 EPHA 的结构功能研究

• 批准号: 8361588
• 负责人: Hans-Guido Wendel
• 金额: $ 1.3万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361588
• 关键词: 6q21; Affect; Alleles; Development; EphA Receptors; Follicular Lymphoma; Funding; Gene Targeting; Grant; Length; Lymphocyte; Lymphoma; Lymphomagenesis; Mass Spectrum Analysis; Methylation; Modeling; Mus; National Center for Research Resources; Oncogenic; Pathway interactions; Principal Investigator; RNA library; Recurrence; Research; Research Infrastructure; Resources; Signal Pathway; Signal Transduction; Source; Structure; Therapeutic Effect; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States National Institutes of Health; analog; cost; insight; macromolecule; mouse model; novel; reconstitution; small hairpin RNA; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In an array CGH study on ~150 follicular lymphomas we found recurrent deletions affecting Chr. 6q21-25 in ~20-25% of cases and increasing with tumor grade. Using a short hairpin RNA (shRNA) library screen we identify EphA as a novel tumor suppressor gene targeted by this deletion. EphA behaves as a classical tumor suppressor and the remaining allele is subject to extensive methylation. Moreover, knockdown of EphA accelerates tumor development in a mouse model of follicular lymphoma. Strikingly, in normal lymphocytes we find expression of truncated and secreted form of EphA, which acts inhibit oncogenic signaling pathways in lymphocytes. Together, these findings point to EphA as a soluble secreted tumor suppressor protein involved in lymphomagenesis and progression. We now propose to a) examine the effects of EphA loss and exogenous reconstitution in murine lymphoma models, b) study the structures of soluble and full length EphA receptors, and c) use mass spectrometry to delineate the signaling consequences of this novel tumor suppressor pathway. We expect our study will provide new insight into the novel EphA tumor suppressor. Notably, this pathway is triggered by a secreted form of EphA, which indicates that administration of exogenous EphA (or analogues) could re-activate this pathway and produce therapeutic effects in tumors.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在对约150例滤泡性淋巴瘤进行的阵列CGH研究中，我们发现了影响Chr的反复缺失。6q21-25在20-25%的病例中表达，并随着肿瘤分级的增加而增加。利用短发夹状RNA(ShRNA)文库筛选，我们确定EphA是一个新的肿瘤抑制基因，它是该缺失的靶点。Epha是一种经典的肿瘤抑制基因，其余的等位基因会发生广泛的甲基化。此外，在滤泡性淋巴瘤的小鼠模型中，EphA基因的敲除会加速肿瘤的发展。值得注意的是，在正常淋巴细胞中，我们发现截短型和分泌型EphA的表达，它的作用是抑制淋巴细胞中的致癌信号通路。总之，这些发现表明EphA是一种可溶性的分泌型肿瘤抑制蛋白，参与了淋巴肿瘤的发生和发展。 我们现在建议a)检测EphA缺失和外源性重建对小鼠淋巴瘤模型的影响，b)研究可溶性和全长EphA受体的结构，以及c)使用质谱学来描述这一新的肿瘤抑制途径的信号后果。 我们期待我们的研究将为新的EphA肿瘤抑制因子提供新的见解。值得注意的是，这一途径是由一种分泌形式的EphA触发的，这表明给予外源性EphA(或类似物)可以重新激活这一途径，并在肿瘤中产生治疗效果。