Melino G, Draoui M, Bernardini S, Bellincampi L, Reichert U, Cohen P
Biochemistry Laboratory, IDI-IRCCS, C10 Department of Experimental Medicine, University of Rome, Tor Vergata, Italy.
Cell Growth Differ. 1996 Jun;7(6):787-96.
Physiologically, the action of insulin-like growth factors (IGFs) is controlled at different levels, from its transcription start by tissue-specific and development-specific transcriptional factors to its degradation by peptidases such as insulin-degrading enzyme (IDE). Since IGF-II is the major autocrine/paracrine growth factor for neuroblastoma cells, we studied the expression and the role of IDE in this system. Here, we show that (a) IDE is expressed in several human neuroectodermal tumor cell lines, including neuroblastoma cell lines; (b) in a neuroblastoma cell line, IDE expression is up-regulated by retinoic acid, a well-known inducer of neuronal differentiation and/or programmed cell death; (c) IDE is probably not the only IGF-degrading enzyme present in these cells, since the activity of a novel thermolysin-like metalloendopeptidase, clearly distinct from IDE, is also detected. The TME activity is inhibited by IGF-I, Des-IGF-I, and IGF-II, and it is down-regulated by retinoic acid. Since retinoic acid plays a relevant role in controlling the growth of these cells and affects the expression of IDE, we have also: (a) identified the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) expressed in these cell lines and (b) by means of synthetic retinoid analogues identified the RAR/RXR isoforms whose activation may be sufficient to induce the expression of the IDE gene. These results provide evidence that complex posttranslational molecular mechanisms participate in the autocrine/paracrine growth control of the IGF-II loop in neuroblastomas involving proteolytic systems.
从生理学角度来看，胰岛素样生长因子（IGFs）的作用在不同水平受到调控，从组织特异性和发育特异性转录因子启动其转录，到胰岛素降解酶（IDE）等肽酶对其进行降解。由于IGF-II是神经母细胞瘤细胞的主要自分泌/旁分泌生长因子，我们研究了IDE在该系统中的表达及其作用。在此，我们发现：（a）IDE在几种人类神经外胚层肿瘤细胞系中表达，包括神经母细胞瘤细胞系；（b）在一种神经母细胞瘤细胞系中，IDE的表达可被视黄酸上调，视黄酸是一种众所周知的神经元分化和/或程序性细胞死亡诱导剂；（c）IDE可能不是这些细胞中唯一存在的IGF降解酶，因为还检测到一种新型嗜热菌蛋白酶样金属内肽酶的活性，该酶与IDE明显不同。该嗜热菌蛋白酶样金属内肽酶（TME）的活性受到IGF-I、脱（1-3）IGF-I和IGF-II的抑制，并被视黄酸下调。由于视黄酸在控制这些细胞的生长中起重要作用并影响IDE的表达，我们还：（a）鉴定了这些细胞系中表达的视黄酸受体（RARs）和类视黄醇X受体（RXRs），以及（b）通过合成类视黄酸类似物鉴定了其激活可能足以诱导IDE基因表达的RAR/RXR亚型。这些结果提供了证据，表明复杂的翻译后分子机制参与了神经母细胞瘤中涉及蛋白水解系统的IGF-II环路的自分泌/旁分泌生长控制。
