TUMOR CELL SYNTHESIS AND SECRETION OF PEPTIDE HORMONES

本研究项目的目的是阐明在肿瘤 内分泌和非内分泌来源的细胞及其正常 前体细胞是合成的分子事件， 调节多肽激素的储存和分泌。 它 与转录、加工和结构有关 编码肽的mRNA和翻译， 翻译后加工，分泌和结构， 肽产品本身。 它主要针对ACTH 和其它阿黑皮素原（POMC）肽。 因为 POMC肽的非垂体肿瘤分泌通常 与降钙素（CT）、精氨酸加压素（AVP）相关 (AVP)和胃泌素释放肽（GRP），因为 促肾上腺皮质激素释放激素（CRH）可能参与 调节异位以及在位POMC肽分泌， 可能是异位分泌本身，肿瘤分泌这些 还将研究多肽激素。 的研究 库欣病犬POMC肽分泌的调节 疾病，一种罕见的人类疾病的常见动物模型，将 完成。 DMS 79的POMC mRNA的结构 人小细胞肺癌细胞将通过 序列测定和/或S1核酸酶或RNA酶作图 不寻常的5'延伸。 根本问题是， 肿瘤异位分泌这些激素， 将通过测量免疫反应性 正常大鼠和正常对照大鼠的POMC肽和可杂交的POMC mRNA 人体组织，以及负责合成它们的细胞， 通过免疫细胞化学和原位mRNA鉴定 组织切片的杂交研究。 成年叙利亚金黄色 仓鼠全身致癌物质二乙基亚硝胺 (DEN)，将进行研究，以确定 神经内分泌细胞包括神经上皮小体（NEB）， 支气管上皮，当刺激增生时， 最终肿瘤由DEN，只是产生不适当的 它们的正常产物CT或开始大量产生 异位POMC肽，AVP或GRP，三个最重要的 肺癌产生的常见肽。 结果将 提供有力的证据支持或反对激素的去抑制 正常细胞或起源不表达的基因。 调控 正常大鼠肾上腺髓质细胞和PC 12分泌POMC的研究 大鼠肾上腺嗜铬细胞瘤细胞将在 分散细胞灌流柱系统。 激动剂和 拮抗剂及其细胞内信号转导途径 将被探索。 灌注系统也将用于测试 对糖皮质激素的相对抵抗 分泌POMC的人垂体的负反馈 引起库欣病的微腺瘤仅仅是 手机号 这些研究的结果将提供新的见解 肽激素合成和分泌的现象 肿瘤细胞。

The objective of this research project is to elucidate in tumor cells of endocrine and nonendocrine origin and in their normal precursor cells the molecular events by which the synthesis, storage, and secretion of polypeptide hormones are regulated. It is concerned with the transcription, processing, and structure of the mRNAs encoding the peptides and the translation, posttranslational processing, secretion, and structure of the peptide products themselves. It is directed primarily at ACTH and the other proopiomelanocortin (POMC) peptides. Because nonpituitary tumor secretion of POMC peptides is often associated with that of calcitonin (CT), arginine vasopressin (AVP), and gastrin-releasing peptide (GRP) and because corticotropin-releasing hormone (CRH) may be involved in regulating ectopic as well as eutopic POMC peptide secretion and may be ectopically secreted itself, tumor secretion of these polypeptide hormones will also be investigated. Studies on the regulation of POMC peptide secretion in the dog with Cushing's disease, a common animal model of a rare human condition, will be completed. The structure of the POMC mRNA from DMS 79 human small cell lung carcinoma cell will be elucidated by sequence determination and/or S1 nuclease or RNase mapping of its unusual 5' extension. The fundamental question whether tumors secrete these hormones ectopically or merely inappropriately will be answered by measuring immunoreactive POMC peptides and Hybridizable POMC mRNA in normal rat and human tissues, and the cells responsible for their synthesis will be identified by immunocytochemical and in situ mRNA hybridization studies on tissue sections. Adult Syrian golden hamsters to which a systemic carcinogen, diethylnitrosamine (DEN), is administered will be studied to determine if the neuroendocrine cells comprising neuroepithelial bodies (NEBs) in bronchial epithelium, when stimulated to hyperplasia and eventually neoplasia by DEN, merely produce inappropriate quantities of their normal product, CT, or begin to produce ectopically POMC peptides, AVP or GRP, three of the most common peptides produced by lung cancers. The results will provide strong evidence for or against derepression of hormonal genes not expressed by the normal cell or origin. Regulation of POMC secretion in normal rat adrenal medullary cells and PC12 rat adrenal pheochromocytoma cells will be examined in a dispersed cell perifusion column system. Both agonists and antagonists and their intracellular signal transduction pathways will be explored. The perfusion system will also be used to test the hypothesis that the relative resistance to glucocorticoid negative feedback in POMC-secreting human pituitary microadenomas causing Cushing's disease is simply a function of cell number. The results of these studies will provide new insights into the phenomenon of peptide hormone synthesis and secretion by tumor cells.