GROWTH FACTOR INVOLVEMENT IN PITUITARY FUNCTION

生长因子参与垂体功能

• 批准号: 2905439
• 负责人: Jeffrey E Kudlow
• 金额: $ 26.56万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2905439
• 关键词: DNA binding protein; DNA damage; binding sites; epidermal growth factor; gene expression; gene targeting; genetic promoter element; genetically modified animals; growth factor receptors; hormone regulation /control mechanism; laboratory mouse; p53 gene /protein; pituitary gland; prolactin; tissue /cell culture; transcription factor; transforming growth factors; tumor suppressor genes

DESCRIPTION: Transforming growth factor-alpha (TGF-alpha), one of the ligands for the epidermal growth factor (EGF) receptor, is expressed in the pituitary gland as well as numerous other tissues. It has been postulated to play a role in the development of pituitary adenomas and cancers in tissues such as breast. TGF-alpha is normally expressed in lactotrophs and this expression is upregulated by estrogen prior to the development of lactotroph hyperplasia. In a transgenic mouse model in which we directed overexpression of TGF alpha to the lactotrophs, lactotroph hyperplasia and adenomata develop. To determine if EGF receptor signaling is required for the pituitary response to pregnancy and estrogen stimulation, we developed a transgenic mouse that expresses a dominant negative EGF receptor in the lactotrophs. The specificity of the growth stimulation to the lactotrophs by the TGF alpha targeted to these cells will be another focus of our investigations. TGF alpha is a general growth factor and the EGF receptor is widely dispersed in the pituitary in cells other than lactotrophs. We therefore propose to investigate how the action of TGF alpha is spatially confined within the pituitary. This question has important implication in development where general growth factor mediate growth responses in specific cell lineages. We propose experiments to test the role of the TGF alpha membrane anchor in the spatial limitation of TGF alpha activity in the pituitary by introducing mutations in the growth factor that either remove the anchor or prevent proteolytic processing. Transgenic mouse models will be created using these mutant TGF alpha precursors. We will also continue our studies of the TGF alpha promoter. We have defined several elements in the TGF alpha promoter which control transcription of this gene in cell cultures. We will extend these studies in transgenic animals to determine the segments of an elements within the TGF alpha promoter that direct expression of the gene to specific tissues such as pituitary, kidney, breast, brain and skin. We will also continue to study the role of p53 in TGF alpha gene expression. We have found that the TGF alpha promoter contains p53 binding sites that confer transcriptional activation upon the TGF alpha gene in response to p53. While a major function of p53 is in tumor suppression, this aspect of p53 function has the paradoxic role of allowing p53 to stimulate cell proliferation in response to DNA damage, thus providing a signal for epithelial repair. We propose to study whether the TGF alpha promoter can be activated by DNA damage in transgenic animals with an intact or knocked-out p53 gene. Together, these studies will test the function of the TGF alpha promoter in vivo.

描述：转化生长因子-Alpha（TGF-Alpha），其中之一 表皮生长因子（EGF）受体的配体在 垂体以及许多其他组织。 它已经假设 在垂体腺瘤和癌症的发展中发挥作用 组织，例如乳房。 TGF-α通常在乳营养素中表达 在发展之前，雌激素上调了这种表达 乳酸营养增生。 在我们指示的转基因鼠标模型中 TGFα的过表达对乳酸营养，乳酸营养增生和 腺瘤发展。 确定是否需要EGF受体信号传导 垂体对怀孕和雌激素刺激的反应，我们发展了 转基因小鼠在表达主要的负EGF受体的转基因小鼠 乳营养素。 生长刺激对乳酸营养的特异性 针对这些细胞的TGFα将是我们的另一个重点 调查。 TGFα是一般生长因子和EGF受体 被广泛分散在垂体中的细胞中以外的其他细胞中。 我们 因此，建议研究TGFα的作用在空间上是如何的 局限于垂体内。 这个问题在 一般生长因子介导特定的增长反应的发展 细胞谱系。 我们提出了测试TGFα的作用的实验 膜锚在TGFα活性的空间限制中 垂体通过在生长因子中引入突变，即 锚或防止蛋白水解加工。 转基因鼠标模型将 使用这些突变体TGFα前体创建。 我们还将继续 我们对TGFα启动子的研究。 我们在 控制该基因在细胞中的转录的TGFα启动子 文化。 我们将在转基因动物中扩展这些研究，以确定 TGF alpha启动子中的元素的细分市场 基因表达对垂体，肾脏等特定组织的表达 乳房，大脑和皮肤。 我们还将继续研究p53在 TGFα基因表达。 我们发现TGF alpha启动子 包含p53结合位点，赋予转录激活 TGFα基因响应p53。 p53的主要功能在 肿瘤抑制，p53功能的这一方面具有矛盾的作用 允许p53刺激细胞增殖，以应对DNA损伤，从而刺激细胞增殖 提供上皮修复的信号。 我们建议研究是否 TGFα启动子可以通过DNA损伤在具有的转基因动物中激活 完整或敲除p53基因。 这些研究将共同​​测试 TGFα启动子在体内的功能。