MOLECULAR MECHANISM OF ACTION OF SOMATOSTATIN

申请人现为加州大学初级教员。 密歇根医学院，他已经证明了长期的承诺 投身于胃肠病学的学术生涯。在过去的几年里，他 一直在山田忠孝博士的指导下进行他的研究。 他一直在探索一些生长抑素抑制 对细胞功能的作用可能是通过抑制表达来实现的 早期反应基因。C-fos和c-jun是最具特色的 这个基因家族的成员。众所周知，他们的产品可以与 相互形成异二聚体转录因子复合体(AP-1)，该复合体 与共有序列TGACTCA的DNA元件特异性结合，并 刺激附近启动子的转录。C-fos和c-jun 似乎参与了几个细胞激活计划，包括 生长和分化以及大量的报告都证实了 抑制c-fos和c-jun活性导致细胞抑制 扩散。生长抑素抑制c-选择素表达的研究 Fos和c-jun，从而抑制AP-L激活的基因转录 (或TPA反应元件，TRE)，然后可能反映一个重要的机制 通过这种方式，生长抑素对细胞的至少部分抑制作用，如 如增殖或分泌，可能是介导的。这个项目有 不仅在基础科学研究领域具有重要意义，而且 也在临床医学领域，因为生长抑素目前 广泛用于治疗多种人类疾病。在他最初的演讲中 研究表明，生长抑素同时抑制c-fos和c-fos C-jun基因表达与AP-L的结合及激活作用 多种蛋白磷酸酶。他还证明了这一效果 生长抑素的水平与荷尔蒙 抑制细胞增殖和胃酸分泌。第一个目标 本申请的目的将是进一步检查 生长抑素对c-fos和c-jun基因表达的影响 这两个基因启动子中的生长抑素反应元件。一个 将尝试克服生长抑素的抑制作用 细胞通过过表达c-fos和c-jun发挥功能。最后，研究将是 目的是确定生长抑素抑制作用的靶基因 C-fos和c-jun基因在胃中的表达。尤其是，一旦 组胺H2受体基因启动子含有一个可能的AP-L位点 由于组胺是一种重要的胃酸促分泌剂，它将是 检测生长抑素是否能够抑制组胺H2受体基因 通过其对AP-L的抑制作用而表达。第二个目标将集中于 生长抑素刺激的蛋白磷酸酶可能 抑制激活c-fos和c-jun的蛋白激酶或导致 C-fos和c-jun分子特定部分的去磷酸化 导致基因转录减弱。

The applicant is currently a junior faculty member at the University of Michigan Medical School who has already demonstrated a long time commitment to a career in academic gastroenterology. Over the past few years he has been conducting his research under the mentorship of Dr. Tadataka Yamada. He has been exploring the possibility that some of somatostatins inhibitory actions on cellular functions might be mediated by inhibition of expression of early response genes. c-fos and c-jun are among the best characterized members of this family of genes. Their products are known to interact with each other to form a heterodimeric transcription factor complex (AP-1) that binds specifically to DNA elements of the consensus sequence TGACTCA and stimulates the transcription of nearby promoters. Both c-fos and c-jun appear to take part in several programs of cellular activation that include growth and differentiation and numerous reports have confirmed that inhibition of c-fos and c-jun activity leads to inhibition of cell proliferation. The ability of somatostatin to inhibit the expression of c- fos and c-jun and thereby inhibit gene transcription activated through AP-l (or TPA response-elements, TRE), might then reflect an important mechanism by which at least some of somatostatin's inhibitory actions on cells, such as proliferation or secretion, might be mediated. This project has important implications not only in the arena of basic science research but also in the field of clinical medicine since somatostatin is currently widely used for the treatment of numerous human diseases. In his initial studies, the PI has demonstrated that somatostatin inhibits both c-fos and c-jun gene expression and AP-l binding and function via activation of multiple protein phosphatases. He has also demonstrated that this effect of somatostatin is paralleled precisely by the ability of the hormone to inhibit both cell proliferation and gastric acid secretion. The first aim of the present application will be directed at further examining the effect of somatostatin on c-fos and c-jun gene expression by defining the presence of somatostatin response elements in the promoters of these two genes. An attempt will be made to overcome the inhibitory effect of somatostatin on cell function by overexpressing c-fos and c-jun. Finally, studies will be conducted to define a target gene for the inhibitory action of somatostatin on c-fos and c-jun gene expression in the stomach. In particular, once the promoter of the histamine H2-receptor gene contains a putative AP- l site and since histamine is an important gastric acid secretagogue, it will be examined whether somatostatin is able to inhibit histamine H2-receptor gene expression through its inhibitory effect on AP-l. The second aim will focus on the possibility that somatostatin stimulated protein phosphatases could inhibit protein kinases that activate c-fos and c-jun or lead to dephosphorylation of specific portions of the c-fos and c-jun molecules resulting in diminished gene transcription.