Inhibition of pancreatic glucagon gene expression in mice bearing a subcutaneous glucagon-producing GLUTag transplantable tumor.
Inhibition of pancreatic glucagon gene expression in mice bearing a subcutaneous glucagon-producing GLUTag transplantable tumor.
复制标题
抑制皮下产生胰高血糖素的 GLUTag 可移植肿瘤小鼠的胰腺胰高血糖素基因表达。
DOI：
10.1210/mend.6.12.1491697
复制
发表时间：
1992
影响因子：
--
通讯作者：
P. Brubaker
中科院分区：
文献类型：
--
作者：
D. Drucker;Y. C. Lee;S. Asa;P. Brubaker
表达胰高血糖素基因-猴病毒-40大t抗原（GLUTag）融合基因的转基因小鼠发生大肠神经内分泌癌。将这种产生胰高血糖素的肿瘤移植到裸鼠体内并可再生形成肿瘤。移植的GLUTag肿瘤表达了大量的胰高血糖素mRNA转录本，并且在肿瘤生长的2-8周内，胰高血糖素mRNA转录本的水平保持不变。可移植肿瘤中胰高血糖素原的翻译后加工过程与原转基因肿瘤相似，胰高血糖素、oxyntomodulin、胰高血糖素、胰高血糖素样肽（1-37）[GLP-1-(1-37)]和GLP-1-(7-37)被释放。荷瘤小鼠血浆胰高血糖素原衍生肽水平进行性升高。血浆中胰高血糖素样免疫反应肽和免疫反应性胰高血糖素水平升高与胰高血糖素mRNA转录物水平显著降低相关，肿瘤生长8周后，Northern blot分析未检测到胰腺中胰高血糖素mRNA转录物水平。在4-8周的荷瘤动物胰腺中，胰高血糖素原衍生肽的合成也被显著抑制。携带胰高血糖素肿瘤6-8周的小鼠内分泌胰腺组织学检查显示，朗格汉斯胰岛的数量和大小明显减少，表现胰高血糖素免疫反应性的细胞数量明显减少。电镜下，残留的a细胞体积小，被压缩在胰岛周围，胞质细胞器发育不全。相比之下，没有肿瘤的对照动物或携带sc - v-jun诱导的纤维肉瘤的小鼠胰高血糖素基因表达和胰岛形态没有变化。血浆胰高血糖素原衍生肽水平升高对小鼠胰腺a细胞功能和胰岛大小的抑制，提示胰高血糖素原衍生肽可能参与了一个负反馈回路，抑制胰高血糖素基因在内分泌胰腺a细胞中的表达。
Transgenic mice that express a glucagon gene-simian virus-40 large T-antigen (GLUTag) fusion gene develop neuroendocrine carcinoma of the large bowel. This glucagon-producing tumor was implanted sc and reproducibly formed tumors in nude mice. The transplanted GLUTag tumor expressed large amounts of proglucagon mRNA transcripts, and the levels of proglucagon mRNA transcripts remained constant during 2-8 weeks of tumor growth. The posttranslational processing of proglucagon in the transplantable tumor resembled that detected in the original transgenic tumor, with the liberation of glicentin, oxyntomodulin, glucagon, glucagon-like peptide (1-37) [GLP-1-(1-37)] and GLP-1-(7-37). Tumor-bearing mice demonstrated progressive elevations in the plasma levels of proglucagon-derived peptides. Elevated plasma levels of glucagon-like immunoreactive peptides and immunoreactive glucagon were associated with a marked reduction in the levels of pancreatic glucagon mRNA transcripts by 4 weeks, and after 8 weeks of tumor growth, the levels of glucagon mRNA transcripts in the pancreas were not detectable by Northern blot analysis. Synthesis of the proglucagon-derived peptides was also significantly suppressed at 4-8 weeks in the pancreas of tumor-bearing animals. Histological examination of the endocrine pancreas in mice carrying the GLUTag tumor for 6-8 weeks demonstrated a marked reduction in the number and size of the islets of Langerhans and a disproportionately greater decrease in the number of cells exhibiting glucagon immunoreactivity. By electron microscopy, the residual A-cells were small, compressed at the periphery of the islets, and had poorly developed cytoplasmic organelles. In contrast, no changes in mouse glucagon gene expression or islet morphology were detected in control animals without tumors or mice carrying a sc v-jun-induced fibrosarcoma. The suppression of pancreatic A-cell function and islet size in mice with elevated plasma levels of the proglucagon-derived peptides raises the possibility that a proglucagon-derived peptide may participate in a negative feedback loop, inhibiting expression of the glucagon gene in the A-cells of the endocrine pancreas.