REGULATION OF GROWTH FACTORS AND MAMMALIAN EMBRYOGENESIS

调节生长因子产生的机制很差， 明白 胚胎癌（EC）细胞，在体外分化 并模仿哺乳动物早期发育的重要阶段， 解决这个问题。 EC细胞的分化抑制了 两种不同的生长因子，一种与成纤维细胞生长因子有关， （称为FGF相关生长因子）和一个与血小板相关的- 衍生生长因子（称为PDGF相关生长因子）。 相反地，EC细胞的分化导致细胞数量的增加， 能够结合血小板源生长因子、成纤维细胞生长因子和其他两种生长因子的受体。 这些 研究结果和其他研究表明，EC细胞及其分化细胞 为研究分子机制提供了一个强大的模型系统， 控制几种生长因子及其受体的产生。 寻找编码FGF相关生长因子的基因 导致发现EC细胞表达KS-FGF基因（ 生长因子的FGF家族，也称为hst）。 另外我们 确定EC细胞的分化显著降低了 KS-FGF mRNA的稳态水平。 根据这些发现，我们 假设FGF相关生长的产生减少 当EC细胞分化时发生的一个因素是由于 KS-FGF基因的转录。 为了验证这一假设，五个具体的 目的：1）分离和测序小鼠KS-1基因的cDNA克隆， FGF基因在EC细胞中的表达，2）确定KS-FGF基因在EC细胞中表达的水平， 基因在EC细胞中受到调控，3）分离并测序用于 KS-FGF，4）检查KS-FGF基因的非编码序列， 调节功能，和5）检查KS-FGF mRNA的区域， 可能的转录后调节功能。 建议的工作 该应用由于几个原因而重要。 首先， 抑制癌基因表达的机制， 广泛的肿瘤细胞和一些卡波西肉瘤细胞 考察 同样重要的是，拟议的工作将有助于解决 我们现有知识的关键差距，即我们对 调节生长因子生产的机制。 在 此外，这项工作将提供一个基础，了解这是如何 癌基因在早期发育过程中受到调节。

The mechanisms that regulate the production of growth factors are poorly understood. Embryonal carcinoma (EC) cells, which differentiate in vitro and mimic important stages of early mammalian development, can be used to address this issue. Differentiation of EC cells suppresses the production of two different growth factors, one related to fibroblast growth factor (referred to as FGF-related growth factor) and one related to platelet- derived growth factor (referred to as PDGF-related growth factor). Conversely, differentiation of EC cells leads to an increase in the number of receptors able to bind PDGF, FGF, and two other growth factors. These findings and others indicate that EC cells and their differentiated cells provide a powerful model system for studying the molecular mechanisms that control the production of several growth factors and their receptors. Efforts to identify the gene that codes for the FGF-related growth factor led tot he finding that EC cells express the gene for KS-FGF (a member of the FGF family of growth factors, also known as hst). In addition, we determined that differentiation of EC cells dramatically reduces the steady-state levels of KS-FGF mRNA. On the basis of these findings, we hypothesize that the reduction in the production of the FGF-related growth factor that occurs when EC cells differentiate is due to a reduction in the transcription of the KS-FGF gene. To test this hypothesis, five Specific AIMS are proposed: 1) Isolate and sequence a murine cDNA clone for the KS- FGF gene expressed in EC cells, 2) determine the level at which the KS-FGF gene is regulated in EC cells, 3) isolate and sequence the murine gene for KS-FGF, 4) examine non-coding sequences of the KS-FGF gene for possible regulatory function(s), and 5) examine regions of the KS-FGF mRNA for possible post-transcriptional regulatory functions. The work proposed in this application is significant for several reasons. First nad foremost, the mechanisms that repress the expression of an oncogene that is expressed by a wide range of tumor cells and by some Kaposi's sarcoma cells will be examined. Equally important, the proposed work will help address a critical gap in our current knowledge, namely, our limited understanding of the mechanisms by which growth factor production is regulated. In addition, this work will provide a basis for understanding how this oncogene is regulated during early development.