Transcriptional regulation of NC precursor formation

描述（由申请人提供）：神经嵴细胞是多能、迁移、组织侵入性细胞，起源于脊椎动物胚胎的外胚层，在脊椎动物身体发育中起核心作用。许多毁灭性的癌症，包括黑色素瘤和神经母细胞瘤，都是神经嵴的癌症。此外，神经嵴细胞与转移性肿瘤细胞具有许多共同的一般特征，并且这两种细胞类型具有共同的关键分子介质，包括Snail家族阻遏物和c-myc。 该提案旨在利用非洲爪蟾系统的相当大的优势，以更好地了解蜗牛相关因子和c-myc在正常神经嵴发育和肿瘤发生中所起的作用，包括获得侵袭性。该基金的目的包括：1）确定神经嵴前体形成、神经嵴迁移和肿瘤细胞上皮间质转化（EMT）过程中Snail家族蛋白不同活性的分子机制; 2）确定c-myc是否通过向靶启动子募集HAT活性来调节神经嵴靶基因的表达，并确定Id 3在神经嵴形成期间是否作为Myc效应子起作用; 3）使用基于cDNA宏阵列的基因发现方法来鉴定神经嵴前体细胞形成过程中c-myc和Snail家族阻遏物的关键转录靶标，以及在神经嵴迁移开始期间，以及4）通过检查这些因子的表达，以及过表达这些因子的作用，在一组上皮肿瘤细胞系中

DESCRIPTION (provided by applicant): Neural crest cells are multi-potent, migratory, tissue-invasive cells that originate in the ectoderm of vertebrate embryos and play a central role in the development of the vertebrate body plan. A number of devastating cancers, including melanoma and neuroblastoma, are cancers of the neural crest. Moreover, neural crest cells share a number of general characteristics with metastatic tumor cells, and these two cell types have key molecular mediators in common, including Snail-family repressors and c-myc. This proposal seeks to exploit the considerable advantages of the Xenopus system in order to better understand the roles played by Snail-related factors and c-myc during normal neural crest development and in tumorigenesis, including the acquisition of invasiveness. The aims of the grant include: 1) determining the molecular mechanisms that underlie the distinct activities of Snail-family proteins during neural crest precursor formation, neural crest emigration, and during epithelial-to-mesenchymal transitions (EMTs) in tumor cells; 2) determining if c-myc regulates the expression of neural crest target genes by recruiting HAT activity to target promoters, and determining if Id3 functions as a Myc-effector during neural crest formation; 3) using cDNA macroarray-based gene discovery methods to identify the key transcriptional targets of c-myc and Snail-family repressors during neural crest precursor cell formation, and during the onset of neural crest migration and 4) testing the hypothesis that such targets will also play roles in tumor progression by examining the expression of these factors, and the effects of over-expressing these factors, in a panel of epithelial tumor cell lines