PROTEIN 4.1 TUMOR SUPPRESSORS IN MENINGIOMA PATHOGENESIS

描述（由申请人提供）：脑膜瘤是最常见的 神经系统肿瘤，并且在老年人，特别是女性中普遍存在。 在分子发病机制和恶性肿瘤中起重要作用的遗传事件 散发性脑膜瘤的进展只是部分特征。到目前为止， 最常检测到的遗传改变是杂合性丢失 (LOH)染色体22 q和神经纤维瘤病2（NF 2）肿瘤的失活 抑制基因，发生在40- 60%的散发性脑膜瘤。述nf 2 基因产物merlin是蛋白质4.1家族的成员， 膜相关蛋白。最近，我们发现了另一种蛋白4.1肿瘤， 抑制基因DAL- 1（在乳腺癌中的差异表达） 肺），约60%的脑膜瘤中丢失。我们建议 蛋白质4.1肿瘤抑制因子DAL-1和Merlin是软脑膜细胞 生长调节剂对脑膜瘤的发展和进展至关重要。 在这项研究中，我们假设DAL-1作为一个独立的， 脑膜瘤发病机制中功能独特的蛋白4.1肿瘤抑制因子。 我们计划通过（1）确定DAL-1发育表达和（2）确定DAL-1发育表达来测试这一点。 亚细胞定位，（2）表征DAL- 1效应蛋白 交互.和（3）分析DAL-1损害细胞生长的能力， 能动性这些研究共同设计，以确定这一作用， 脑膜瘤肿瘤发生和发展中的新的生长调节因子家族。

DESCRIPTION (Provided by applicant): Meningiomas are among the most common nervous system tumors and are prevalent in older adults, particularly women. The genetic events important in the molecular pathogenesis and malignant progression of sporadic meningiomas are only partially characterized. To date, the most frequently detected genetic alterations are loss of heterozygosity (LOH) on chromosome 22q and inactivation of the neurofibromatosis 2 (NF2) tumor suppressor gene, occurring in 40-60 percent of sporadic meningiomas. The NF2 gene product, merlin, is a member of the Protein 4.1 family of membrane-associated proteins. Recently, we identified another Protein 4.1 tumor suppressor gene, DAL- 1 (Differentially expressed in Adenocarcinoma of the Lung), that is lost in approximately 60 percent of meningiomas. We propose that the Protein 4.1 tumor suppressors, DAL-1 and merlin, are leptomeningeal cell growth regulators critical to the development and progression of meningiomas. In this grant, we hypothesize that DAL-1 operates as an independent and functionally distinct Protein 4.1 tumor suppressor in meningioma pathogenesis. We plan to test this by (1) determining DAL-l developmental expression and subcellular localization, (2) characterizing DAL- 1 effector protein interactions. and (3) analyzing the ability of DAL-1 to impair cell growth and motility. These studies are collectively designed to define the role of this novel family of growth regulators in meningioma tumorigenesis and progression.