Transcriptional regulation of NC precursor formation

描述(申请人提供)：神经脊细胞是起源于脊椎动物胚胎外胚层的多能、迁移性、组织侵袭性细胞，在脊椎动物身体计划的发展中起着核心作用。许多毁灭性的癌症，包括黑色素瘤和神经母细胞瘤，都是神经脊癌。此外，神经脊细胞与转移性肿瘤细胞有许多共同的一般特征，这两种细胞类型都有关键的分子介质，包括蜗牛家族抑制因子和c-myc。 这项建议旨在利用非洲爪哇系统的相当大的优势，以便更好地了解蜗牛相关因子和c-myc在正常神经脊发育和肿瘤发生(包括获得侵袭性)中所起的作用。该基金的目标包括：1)确定蜗牛家族蛋白在神经峰前体形成、神经峰迁移和肿瘤细胞上皮向间充质转化(EMT)过程中不同活性的分子机制；2)确定c-myc是否通过招募HAT活性到靶启动子来调节神经峰靶基因的表达，以及确定ID3在神经峰形成过程中是否作为Myc效应因子发挥作用；3)使用基于cdna大阵列的基因发现方法，确定c-myc和蜗牛家族抑制物在神经峰前体细胞形成和神经峰迁移开始期间的关键转录靶点，以及4)通过检测这些因子在一组上皮性肿瘤细胞系中的表达以及过度表达这些因子的影响，来检验这些靶点也将在肿瘤进展中发挥作用的假设。

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