Meester-Smoor Magda A, Molijn Anco C, Zhao Yixian, Groen Nicole A, Groffen Cora A H, Boogaard Merel, van Dalsum-Verbiest Diny, Grosveld Gerard C, Zwarthoff Ellen C
Department of Pathology, Erasmus MC-Josephine Nefkens Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
J Mol Endocrinol. 2007 Feb;38(1-2):113-25. doi: 10.1677/jme.1.02110.
The IGF-binding protein (IGFBP) family consists of six proteins that are expressed and secreted in different tissues. The proteins are regulators of physiological processes throughout the body by modulating the activity of IGF-I and IGF-II. In this article, we describe the coordinated expression of IGFBP5 and MN1 in meningiomas. MN1 is a transcriptional co-activator and we show that MN1 stimulates the IGFBP5 promoter in Hep3B cells. A CACCC-containing sequence, located 140 bp upstream of the transcription start site of the promoter, is required for MN1 action. This sequence matches with the CACCCAC consensus sequence that was selected in an oligonucleotide selection assay performed for MN1. The CACCC element has also been shown to be important for induction of the IGFBP5 promoter by retinoic acid (RA) and progesterone (Pg). We were unable to confirm the effect of Pg on the promoter in Hep3B and U2-osteosarcoma cells regardless of the presence of MN1. On the other hand, we show that induction of the promoter by RA depends on co-expressed MN1 in Hep3B cells. MN1TEL, a leukemia-related fusion protein containing parts of the MN1 and TEL (ETV6) genes, is capable of stimulating the IGFBP5 promoter but is unable to cooperate with RA in Hep3B cells. This suggests that the effects of RA can be negatively affected in leukemias caused by MN1TEL.
胰岛素样生长因子结合蛋白（IGFBP）家族由六种在不同组织中表达和分泌的蛋白质组成。这些蛋白质通过调节IGF-I和IGF-II的活性，成为全身生理过程的调节因子。在本文中，我们描述了IGFBP5和MN1在脑膜瘤中的协同表达。MN1是一种转录共激活因子，我们发现MN1在Hep3B细胞中刺激IGFBP5启动子。启动子转录起始位点上游140 bp处的一个含CACCC的序列是MN1发挥作用所必需的。该序列与在针对MN1进行的寡核苷酸筛选试验中选择的CACCCAC共有序列相匹配。CACCC元件也已被证明对维甲酸（RA）和孕酮（Pg）诱导IGFBP5启动子很重要。无论是否存在MN1，我们都无法在Hep3B和U2骨肉瘤细胞中证实Pg对启动子的影响。另一方面，我们发现RA对启动子的诱导取决于Hep3B细胞中共表达的MN1。MN1TEL是一种与白血病相关的融合蛋白，包含MN1和TEL（ETV6）基因的部分序列，能够刺激IGFBP5启动子，但在Hep3B细胞中无法与RA协同作用。这表明在由MN1TEL引起的白血病中，RA的作用可能会受到负面影响。
