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.
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