APC IN NEURONAL DIFFERENTIATION & BRAIN TUMOR FORMATION

髓母细胞瘤(MB)是一种发生在小脑的肿瘤，是最常见的 儿童常见的恶性脑瘤，但对此知之甚少 基因成分(S)，参与甲基溴发育或 进步。一种可能的甲基溴遗传基础已经由 结肠腺瘤性息肉病基因突变的鉴定 在有结肠癌易感性的患者中 神经上皮细胞的发病率显著高于平均水平 肿瘤。APC是一种肿瘤抑制因子，常在家族性和非家族性肿瘤中改变 散发性结肠癌，但其在MB中的作用尚未完全 调查过了。APC基因外显子1-15尚未发现突变，因此 远，与甲基溴相关。乔安娜·格罗登博士，这份申请书 共同发起人，已经在APC基因中发现了四个新的5‘外显子，它们给出了 然而，上升到八种在大脑中占主导地位的APC亚型， 增加了脑瘤是由5‘基因突变引起的可能性 外显子。此外，通过与格罗登博士的合作，我们发现MB 细胞株不表达含5‘外显子的APC亚型。这 提案的重点是确定哪些APC异构体在 正常发育的和成人的小脑，而且一直丢失 单位：MB。以正常小脑为特征，但不是MB的亚型将是 将其导入MB细胞系以确定其表达是否发生改变 亚甲基溴的侵袭性或致瘤性。最后，将描述 与5‘APC外显子编码的蛋白质相互作用的蛋白质 努力确定APC可能通过什么机制发挥肿瘤抑制作用 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.