APC IN NEURONAL DIFFERENTIATION & BRAIN TUMOR FORMATION

髓母细胞瘤（MB），一种发生在小脑的肿瘤，是最常见的肿瘤。 常见的恶性脑肿瘤的儿童，但鲜为人知的是， 参与MB发育或 进展一个可能的遗传基础，为MB已建立了由 腺瘤性结肠息肉病（APC）基因突变的鉴定 在具有结肠癌易感性的患者中， 神经上皮细胞的平均发病率明显高于 肿瘤APC是一种肿瘤抑制因子，通常在家族性和 散发性结肠癌，但其在MB中的作用尚未完全 研究了APC基因外显子1-15的突变尚未发现， 与MB相关。乔安娜格罗登博士，这份申请 共同发起人，已经确定了APC基因中的四个新的5'外显子， 然而，在大脑中占主导地位的八种APC亚型， 脑肿瘤可能是由5' 外显子此外，与格罗登博士合作，我们发现MB 细胞系不表达含有5'外显子的APC亚型。这 一项提案的重点是确定哪些APC亚型表达于 正常发育和成年小脑， 单位为MB。表征正常小脑的亚型，但不是MB， 转染到MB细胞系中，以确定它们的表达是否改变 MB的侵袭性或致瘤性。最后，将描述 与由5' APC外显子编码的蛋白质相互作用的蛋白质， 努力确定APC通过何种机制可能作为肿瘤抑制因子发挥作用， 在神经系统的细胞中。

Medulloblastoma (MB), a tumor that arises in the cerebellum, is the most common malignant brain tumor of childhood, yet little is known about the genetic element(s) that is(are) involved in either MB development or progression. A possible genetic basis for MB has been established by the identification of mutations in the adenomatous polyposis coli (A PC) gene in patients that have a predisposition for colon carcinoma coupled with a significantly greater than average incidence of neuroepithelial neoplasias. APC is a tumor suppressor commonly altered in familial and sporadic colon carcinoma, but its role in MB has not been fully investigated. Mutations in APC gene exons 1-15 have not been found, thus far, to correlate with MB. Dr. Joanna Groden, this applications' cosponsor, has identified four novel 5' exons in the APC gene that give rise to eight APC isoforms that predominate in brain, however, giving rise to the possibility that brain tumors result from mutations in 5' exons. Moreover, in collaboration with Dr. Groden, we have found that MB cell lines do not express the 5' exon-containing APC isoforms. This proposal is focused on identifying which APC isoforms are expressed in normal developing and adult cerebellum and which, consistently, are lost in MB. Isoforms that characterize normal cerebellum, but not MB, will be transfected into MB cell lines to determine if their expression alters the invasiveness or tumorigenicity of MB. Finally, will characterize proteins that interact with proteins encoded by the 5' APC exons in efforts to determine by what mechanism APC may act as a tumor suppressor in cells of the nervous system.