Differentiation of Pancreatic Endocrine Cells

1)建立模型细胞系统，研究胰腺内分泌细胞的分化。2)利用该系统，我们发现激活素A和β细胞素（BTC）可将淀粉酶分泌细胞转化为胰岛素分泌细胞。3)我们还发现肝细胞生长因子（HGF）复制了BTC的作用。4)在AR42J细胞中，BTC有特异性的结合位点。BTC的结合被未标记的BTC取代，但EGF的效力要小得多。BTC结合ErbB1和另一个190 KDa的MW蛋白，该蛋白可能是EGF受体家族的新成员。BTC诱导ErbB1、ErbB2、ErbB4和190kda蛋白酪氨酸磷酸化。5)诱导分化的活性被MAP激酶途径的抑制剂阻断，而不被Pl - 3激酶途径的抑制剂阻断。此外，转染具有组成活性MAP激酶的cDNA诱导Ar42J细胞分化。相反，转染MAP酶磷酸酶的cDNA会阻断分化。MAP激酶的激活是hgf诱导AR42J细胞分化的必要条件和充分条件。6)我们通过差异显示检测了AR42J细胞向非胰岛素生成细胞分化过程中表达的基因。激活素A和BTC诱导了25个基因的表达，其中10个是独特基因。其中一些基因的表达被MAP激酶抑制剂阻断。因此，这些基因与AR42J细胞的分化密切相关。

1) We established a model cell system to study the differentiation of pancreatic endocrine cells.2) Using this sytem, we found that activin A and betacellulin (BTC) convert amylase secreting cells into insulin-secreting cells.3) We also found that hepatocyte growth factor (HGF) reproduce the effect of BTC.4) In AR42J cells, there specific binding sites to BTC.The binding of BTC is replaced by unlabeled BTC but EGF is much less potent. BTC binds to ErbB1 and another protein of MW of 190 KDa, which may be a new member of the EGF receptor family. BTC induced tyrosine phosphorylation of ErbB1, ErbB2, ErbB4 and the 190 KDa protein.5) The differentiation-inducing activity is blocked by an inhibitor of the MAP knase pathway but not by an inhibitor of the Pl 3-kinase pathway. In addition, transfection of Ar42J cells with cDNA for constitutively active MAP kinase kinase induced differentiation. Conversely, transfection of cDNA for MAP inase phosphatase blocked differentiation. Activation of MAP kinase is neccesry and sufficient for the HGF-induced differentiation of AR42J cells.6) We examine the genes expressed during the differentiation of AR42J cells inot insulin-producing cells by differential display. Activin A and BTC induced the expression of 25 genes, 10 of which are unique ones. Expression of some of them was blocked by an inhibitor of MAP kinase. Therefore, these genes are cloosely associated with differentiation of AR42J cells.