ALPHA-1 ADRENORECEPTOR, RAS P21, AND LIVER REGENERATION

我们已经证明了α-L肾上腺素能受体直接作用于 大鼠肝细胞增强刺激的DNA合成(Science 227：749-51 (1985))，这种受体也参与了早期的刺激 2/3肝部分切除后大鼠肝脏再生DNA合成的变化。 在复制前阶段的关键时刻，α1受体是 膜磷脂酰肌醇的解偶联(其通常的第二次 信使途径)，并且这种形式的受体似乎是 负责生长调节活动。此外，在 再生肝脏，这种解偶联之前是下降 免疫反应膜p21，细胞ras家族的产物 原癌基因。 拟议的项目将研究由 α-肾上腺素能受体在大鼠肝细胞生长中的作用 受体解偶联的意义，寻找其他第二信使 这些受体所使用的通路，并确定在多大程度上 肝细胞增殖模型(活体肝再生和阿尔法， 在原代培养中刺激DNA合成)具有可比性。这些研究 还将研究p21蛋白在这两种模型中的作用，并探索 它们中的一个或多个与字母1之间是否存在链接 受体。 阿尔法1受体在组织中普遍存在的性质，最近 鉴定与癌基因产物相似的受体(例如血管紧张素 和5-羟色胺受体)，以及ras仍然神秘的作用 蛋白质，其基因是最常见的激活的 人类癌症中的致癌基因，表明这将是一个独特的 有研究价值的模型。

We have demonstrated that the alpha l-adrenergic receptor acts directly on rat hepatocytes to enhance stimulated DNA synthesis (SCIENCE 227:749-51 (1985)), and that this receptor is also involved in the early stimulation of regenerative DNA synthesis in rat liver after 2/3 partial hepatectomy. At a crucial time in the prereplicative phase, the alpha 1 receptor is uncoupled from turnover of membrane phosphatidylinositol (its usual second messenger pathway), and it appears that this form of the receptor is responsible for growth-regulating activities. Additionally, in regenerating liver, this uncoupling is preceded by a fall in immunoreactive membrane p2l, the product of the ras family of cellular proto-oncogenes. The proposed project would examine the mechanism of stimulation by the alpha adrenergic receptor in rat hepatocellular growth, to understand the significance of receptor uncoupling, to seek other second messenger pathways used by these receptors, and to determine to what degree two models of hepatocyte proliferation (liver regeneration in vivo and alpha, stimulated DNA synthesis in primary culture) are comparable. These studies would also examine the role of p2l proteins in both models, and explore whether a link exists between one or more of them and the alpha 1 receptor. The ubiquitous nature of the alpha 1 receptor in tissues, the recent identification of similar receptors as oncogene products (e.g. angiotensin and serotonin receptors) and the still mysterious role of the ras proteins, genes for which are among the most commonly activated of oncogenes in human cancers, suggest that this will be a singularly valuable model to study.