GENE TRAPPING TGF BETA TARGETS IN BREAST EPITHELIAL CELL

转化生长因子-β是一种多功能细胞因子，对正常上皮细胞具有强大的抗有丝分裂原作用。转化后的细胞常常失去转化生长抑制因子-β的生长抑制作用，从而产生转化生长因子-β，作为局部免疫抑制和血管生成因子。因此，转化生长因子-β早期通过维持细胞生长的正常平衡作为肿瘤抑制因子，后来通过促进血管生成和抑制宿主对转化细胞的免疫反应而作为肿瘤促进剂发挥作用。虽然关于转化生长因子-β细胞表面受体的信号如何转化为基因表达的变化已经了解很多，但对转化生长因子-β信号转导的靶点却知之甚少。很少有可能被转化生长因子-β上调或下调的基因被识别出来，而且转化生长因子-β调控生长所必需的关键靶点还没有完全确定。我们的长期目标是对正常乳腺上皮细胞中受转化生长因子-β调控的基因进行分类和鉴定，并确定其中哪些基因对于维持由转化生长因子-β控制的正常细胞内稳态是必不可少的。我们的不足之处在于，少数几组或几类基因的转录调控将是介导转化生长因子-β生长抑制效应的关键，而其他基因将是转移或其他效应的关键。我们将在转化的、非致癌的乳腺上皮细胞中使用基因捕获策略，以确定那些对转化生长因子-β调控生长和致癌至关重要的基因。

Transforming growth factor beta (TGF-beta) is a multifunctional cytokine that acts as a powerful anti-mitogen for normal epithelial cells. Growth inhibition by TGF-beta is often lost in transformed cells, which can then produce TGF-beta which acts as a local immunosuppressive and angiogenic factor. Thus, TGF-beta acts early as a tumor suppressor by maintaining a normal balance of cell growth, and later as a tumor promoter by increasing angiogenesis and suppressing host immune responses to transformed cells. Although much has been learned about how signals from TGF-beta cell surface receptors are transduced into changes in gene expression, little is known about the targets of TGF-beta signaling. Few of the genes likely to be up or down regulated by TGF-beta have been identified, and the critical targets necessary for regulation of growth by TGF-beta have not been fully defined. Our long term goal is to catalogue and identify the genes regulated by TGF-beta in normal breast epithelial cells, and to determine which of those genes is essential for maintenance of normal cellular homeostasis controlled by TGF-beta. Our hyposthesis is that transcriptional regulation of a few sets or classes of genes will be essential to mediating TGF-beta growth inhibitory effects, and that others will be essential for metastasis or other effects. We will use a gene trapping strategy in transformed, non-tumorigenic breast epithelial cells in order to identify those genes essential for TGF-beta regulation of growth and carcinogenesis.