Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells
Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells
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DOI：
10.1053/gast.2002.33594
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发表时间：
2002-06-01
期刊：
影响因子：
29.4
通讯作者：
Schmid, RM
中科院分区：
文献类型：
--
作者：
Wagner, M;Weber, CK;Schmid, RM
背景与目的：表皮生长因子受体家族及其配体在胰腺癌中经常过度表达。为了比较转化生长因子(TGF)-α和两用调节素(AR)对胰腺外分泌生长和分化的生物学效应，我们在弹性酶启动子的控制下建立了高表达AR的转基因小鼠。方法：两个独立产生的转基因小鼠系在胰腺中高表达50、43、28、26和16千道尔顿AR形式。结果：形态学和免疫组织化学检查显示这些小鼠的小叶内管和中央腺泡细胞对AR有反应而增殖。AR转基因小鼠胰管细胞中Ras、ERK1/2、细胞周期蛋白D/CDK4、细胞周期蛋白E/CDK2活性和G1/S进程均增强。与转化生长因子-α转基因小鼠相比，AR既不能诱导肾小管复合体的形成，也不能引起强烈的纤维化反应。AR可诱导小鼠肾小管上皮细胞表达ErbB2，而转化生长因子-α可导致肾小管复合体内EGF受体的过度表达。此外，AR和转化生长因子-α在体外对分离的腺泡细胞分化的影响与体内相似。结论：AR分别通过激活RAS、CDK2和CDK4选择性地诱导小管细胞有丝分裂反应。密切相关的EGF受体配体AIR和TGF-α在体内胰腺外分泌中过表达时，表现出不同的生物学效应。
Background & Aims: The epidermal growth factor (EGF) receptor family and the corresponding ligands are frequently overexpressed In pancreatic cancer. To compare the biological effects of transforming growth factor (TGF)-alpha and amphiregulin (AR) on growth and differentiation of the exocrine pancreas, we have generated transgenic mice overexpressing AR under control of the elastase promoter. Methods: Two independently generated transgenic mouse lines overexpress 50-, 43-, 28-, 26-, and :16-kilodalton AR forms in the pancreas. Results: Morphologic and immunohistochemical examinations suggest that small Intralobular duct and centroacinar cells proliferate In response to AR In these mice. AR transgenic mice display Increased Ras, Erk1/2, cyclin D/CDK4, and cyclin E/CDK2 activity and G1/S progression In pancreatic duct cells. In contrast to TGF-alpha transgenic mice, AR neither induced tubular complex formation nor elicited a strong fibrogenic response. AR induced a slight Induction of ErbB2 on duct cells, whereas TGF-alpha resulted in overexpression of the EGF receptor In cells within tubular complexes. Furthermore, AR and TGF-alpha displayed different effects on differentiation of Isolated acini In vitro comparable to the situation In vivo. Conclusions: These data suggest that AR Induces a mitogenic response selectively In small duct cells through activation of Ras, CDK2, and CDK4, respectively. The closely related EGF receptor ligands, AIR and TGF-alpha, display different biological effects when overexpressed In the exocrine pancreas in vivo.