GROWTH FACTOR INVOLVEMENT IN PITUITARY FUNCTION

描述：转化生长因子-α(转化生长因子-α)， 表皮生长因子(EGF)受体的配体在 脑垂体腺以及许多其他组织。这是一种假设 在脑下垂体腺瘤和癌症的发展中发挥作用 乳房等组织。转化生长因子-α通常在哺乳细胞中表达，并且 这种表达在发生之前就被雌激素上调。 催乳素增生症。在我们指导的转基因小鼠模型中 转化生长因子α过度表达对乳汁滋养细胞、乳汁增生和乳汁分泌的影响 腺瘤形成。确定是否需要EGF受体信号转导 垂体对怀孕和雌激素刺激的反应，我们开发了一种 表达显性负EGF受体的转基因小鼠 乳酸菌。刺激生长对乳酸菌的专一性 靶向这些细胞的转化生长因子α将是我们研究的另一个重点 调查。转化生长因子α是一种通用的生长因子和EGF受体 广泛分布在脑下垂体细胞中，而不是乳汁滋养细胞。我们 因此建议研究转化生长因子α的作用是如何在空间上 局限在脑下垂体内。这个问题在……中具有重要意义 一般生长因子在特定情况下调节生长反应的发展 细胞谱系。我们建议进行实验来测试转化生长因子α的作用。 膜锚定对转化生长因子α活性的空间限制 通过在生长因子中引入突变来移除 锚定或阻止蛋白质降解处理。转基因小鼠模型将 是用这些突变的转化生长因子α前体创造的。我们也会继续 我们对转化生长因子α启动子的研究。我们在中定义了几个元素 控制细胞内该基因转录的转化生长因子α启动子 文化。我们将在转基因动物中扩展这些研究，以确定 转化生长因子α启动子内的元件片段 该基因在特定组织中的表达，如垂体、肾脏、 乳房、大脑和皮肤。我们还将继续研究P53在 转化生长因子α基因表达。我们发现转化生长因子α启动子 包含P53结合位点，赋予转录激活 转化生长因子α基因对P53的反应。虽然P53的主要功能是在 肿瘤抑制，这方面的P53功能具有矛盾的作用 允许p53刺激细胞增殖以应对DNA损伤，因此 为上皮修复提供信号。我们建议研究 转基因动物体内DNA损伤可激活转化生长因子α启动子 完整或敲除的p53基因。总而言之，这些研究将测试 转化生长因子α启动子在体内的作用。

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.