Jamal A-M, Lipsett M, Hazrati A, Paraskevas S, Agapitos D, Maysinger D, Rosenberg L
Department of Surgery, Research Institute of the McGill University Health Center, Montreal, Canada.
Cell Death Differ. 2003 Sep;10(9):987-96. doi: 10.1038/sj.cdd.4401266.
Phenotypic change of adult pancreatic islets has been implicated in the development of certain pancreatic cancers and in islet transplant failure. The aim of this study was to characterize intracellular events that mediate changes in adult islet phenotype. Using an in vitro islet-to-duct transformation model, canine islets were induced to undergo phenotypic transformation to duct-like epithelial structures through a two-stage process. Stage one was characterized by widespread islet cell apoptosis associated with the formation of cavitary spaces within the islets. During this stage, c-Jun N-terminal regulated kinase (JNK) and caspase-3 activities were elevated, while extracellular signal-regulated kinase (ERK) and Akt activities were decreased. The second stage of the process was characterized by an inversion in the balance in activity between these signal transduction pathways and by a concomitant decrease in apoptosis. The transformed islets were no longer immunoreactive for islet cell hormones, but expressed the duct epithelial cell marker CK-AE1/AE3. In contrast to islet cells, these duct epithelial cells were highly proliferative. To clarify the role of the identified changes in signal transduction events, we performed additional studies using pharmacological inhibitors of enzyme activity and demonstrated that inhibition of JNK and caspase-3 activity prevented cystic transformation. Our results indicate that the balance in signaling activity between ERK/Akt and JNK/caspase-3 appears to be an important regulator of islet cell death and differentiation.
成年胰腺胰岛的表型变化与某些胰腺癌的发生及胰岛移植失败有关。本研究的目的是描述介导成年胰岛表型变化的细胞内事件。利用体外胰岛向导管转化模型，通过两阶段过程诱导犬胰岛向导管样上皮结构进行表型转化。第一阶段的特征是广泛的胰岛细胞凋亡，伴有胰岛内空洞空间的形成。在此阶段，c-Jun氨基末端激酶（JNK）和半胱天冬酶-3活性升高，而细胞外信号调节激酶（ERK）和Akt活性降低。该过程的第二阶段的特征是这些信号转导途径之间活性平衡的逆转以及凋亡的同时减少。转化后的胰岛不再对胰岛细胞激素产生免疫反应，但表达导管上皮细胞标志物CK-AE1/AE3。与胰岛细胞不同，这些导管上皮细胞具有高度增殖性。为了阐明信号转导事件中所确定变化的作用，我们使用酶活性的药理学抑制剂进行了额外的研究，并证明抑制JNK和半胱天冬酶-3活性可防止囊性转化。我们的结果表明，ERK/Akt和JNK/半胱天冬酶-3之间的信号活性平衡似乎是胰岛细胞死亡和分化的重要调节因子。
