Curry Christine L, Reed Laura L, Nickoloff Brian J, Miele Lucio, Foreman Kimberly E
Department of Pathology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153-5385, USA.
Lab Invest. 2006 Aug;86(8):842-52. doi: 10.1038/labinvest.3700442. Epub 2006 May 29.
Our laboratory has recently demonstrated constitutive activation of the Notch signaling pathway in Kaposi's sarcoma tumor cells. As endothelial cells (EC) are believed to be the progenitor of these tumor cells, this study was designed to examine the effect of Notch activation on normal human EC. Recent reports suggest Notch activation induces EC growth arrest, and that this growth arrest may be linked to the establishment or maintenance of EC quiescence, the phenotype seen in contact-inhibited EC lining the vasculature. To gain further insight into Notch activation and quiescence, we first confirmed that Notch activation induced EC growth arrest. Next, we examined Notch activation in confluent, growth arrested EC (mimicking the cells lining the vasculature). In contrast to previous reports, we found confluent EC possess lower levels of activated Notch compared to proliferating control cells. Interestingly, these cells express elevated levels of Hes-1 protein (an immediate downstream target of Notch signaling) despite decreased Notch activation. Under these conditions, Hes-1 expression was mediated, at least in part, by a Notch-independent mechanism involving c-jun N-terminal protein kinase (JNK) signaling. This is the first report, to our knowledge, that JNK signaling can modulate Hes-1 expression in a Notch-independent manner.
我们实验室最近证明了卡波西肉瘤肿瘤细胞中Notch信号通路的组成性激活。由于内皮细胞（EC）被认为是这些肿瘤细胞的祖细胞，本研究旨在检测Notch激活对正常人EC的影响。最近的报告表明，Notch激活会诱导EC生长停滞，并且这种生长停滞可能与EC静止状态的建立或维持有关，这种表型见于血管系统中接触抑制的EC。为了进一步深入了解Notch激活与静止状态，我们首先证实了Notch激活会诱导EC生长停滞。接下来，我们检测了汇合的、生长停滞的EC（模拟血管系统内衬细胞）中的Notch激活情况。与之前的报告相反，我们发现与增殖的对照细胞相比，汇合的EC中活化的Notch水平较低。有趣的是，尽管Notch激活减少，但这些细胞中Hes-1蛋白（Notch信号的直接下游靶点）的表达水平却升高。在这些条件下，Hes-1的表达至少部分是由一种不依赖Notch的机制介导的，该机制涉及c-jun氨基末端蛋白激酶（JNK）信号传导。据我们所知，这是第一份关于JNK信号传导可以不依赖Notch方式调节Hes-1表达的报告。
