PROTEIN 4.1 TUMOR SUPPRESSORS IN MENINGIOMA PATHOGENESIS

描述(申请人提供)：脑膜瘤是最常见的 神经系统肿瘤，多见于老年人，尤其是女性。 遗传事件在分子发病机制和恶性疾病中的重要作用 散发性脑膜瘤的进展仅是部分特征。到目前为止， 最常见的基因改变是杂合性丢失。 染色体22q上(LOH)与神经纤维瘤病2(NF2)瘤的失活 抑制基因，出现在40%-60%的散发性脑膜瘤中。NF2 基因产物Merlin是蛋白4.1家族的成员 膜相关蛋白。最近，我们发现了另一个蛋白4.1肿瘤 抑癌基因DAL-1(在腺癌中的差异表达) 肺部)，大约60%的脑膜瘤中缺失。我们建议 蛋白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。 在这项拨款中，我们假设DAL-1作为一个独立的和 脑膜瘤发病机制中的功能差异蛋白4.1肿瘤抑制因子。 我们计划通过(1)测定DAL-L的发育表达和 (2)DAL-1效应蛋白的亚细胞定位 互动。(3)分析DAL-1对细胞生长的抑制作用 能动性。这些研究旨在共同定义这一角色 脑膜瘤发生和发展中的生长调节因子新家族。

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.