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首页> 外文期刊>Journal of Cellular Physiology >Induced overexpression of protein kinase D1 stimulates mitogenic signaling in human pancreatic carcinoma PANC-1 cells.
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Induced overexpression of protein kinase D1 stimulates mitogenic signaling in human pancreatic carcinoma PANC-1 cells.

机译：诱导超表达的蛋白激酶D1刺激促有丝分裂的信号在人类胰脏癌PANC-1细胞。

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摘要

Neurotensin (NT) stimulates protein kinase D1 (PKD1), extracellular signal regulated kinase (ERK), c-Jun N-terminal Kinase (JNK), and DNA synthesis in the human pancreatic adenocarcinoma cell line PANC-1. To determine the effect of PKD1 overexpression on these biological responses, we generated inducible stable PANC-1 clones that express wild-type (WT) or kinase-dead (K618N) forms of PKD1 in response to the ecdysone analog ponasterone-A (PonA). NT potently stimulated c-Jun Ser(63) phosphorylation in both wild type and clonal derivatives of PANC-1 cells. PonA-induced expression of WT, but not K618N PKD1, rapidly blocked NT-mediated c-Jun Ser(63) phosphorylation either at the level of or upstream of MKK4, a dual-specificity kinase that leads to JNK activation. This is the first demonstration that PKD1 suppresses NT-induced JNK/cJun activation in PANC-1 cells. In contrast, PKD1 overexpression markedly increased the duration of NT-induced ERK activation in these cells. The reciprocal influence of PKD1 signaling on pro-mitogenicERK and pro-apopotic JNK/c-Jun pathways prompted us to examine whether PKD1 overexpression promotes DNA synthesis and proliferation of PANC-1 cells. Our results show that PKD1 overexpression increased DNA synthesis and cell numbers of PANC-1 cells cultured in regular dishes or in polyhydroxyethylmethacrylate [Poly-(HEMA)]-coated dishes to eliminate cell adhesion (anchorage-independent growth). Furthermore, PKD1 overexpression markedly enhanced DNA synthesis induced by NT (1-10 nM). These results indicate that PKD1 mediates mitogenic signaling in PANC-1 and suggests that this enzyme could be a novel target for the development of therapeutic drugs that restrict the proliferation of these cells.
机译：神经降压素(NT)刺激蛋白激酶D1(PKD1),细胞外信号调节激酶(ERK) c-Jun n端激酶(物)和DNA合成在人类胰腺腺癌细胞系PANC-1。在这些生物反应过度,我们诱导生成稳定PANC-1克隆表达野生型(WT)或kinase-dead (K618N)形式的PKD1的蜕皮激素模拟ponasterone-A (PonA)。c-Jun Ser野生型(63)磷酸化和克隆衍生品PANC-1细胞。PonA-induced WT的表达,但不是K618NPKD1,迅速封锁NT-mediated c-Jun爵士(63)磷酸化水平的或MKK4的上游dual-specificity激酶导致物激活。PKD1抑制NT-induced示范物/ cJun激活PANC-1细胞。PKD1超表达明显增加了NT-induced ERK激活在这些时间细胞。pro-mitogenicERK和pro-apopotic物/ c-Jun途径促使我们检查是否PKD1超表达促进DNA合成和PANC-1细胞的扩散。DNA合成,PKD1过度增加PANC-1细胞数量和细胞培养定期在polyhydroxyethylmethacrylate菜肴或[聚-(-)]涂布菜肴消除细胞粘连(anchorage-independent增长)。此外,PKD1明显过度增强引起的DNA合成NT(1 - 10海里)。这些结果表明,PKD1介导促有丝分裂的信号在PANC-1和暗示这种酶可以是一个新的目标发展限制的治疗药物这些细胞的扩散。

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