Inhibition of a protein-protein interaction between INI1 and c-Myc by small peptidomimetic molecules inspired by Helix-1 of c-Myc: identification of a new target of potential antineoplastic interest
Inhibition of a protein-protein interaction between INI1 and c-Myc by small peptidomimetic molecules inspired by Helix-1 of c-Myc: identification of a new target of potential antineoplastic interest
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DOI：
10.1096/fj.06-7082com
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发表时间：
2007-04-01
期刊：
影响因子：
4.8
通讯作者：
Parodi, S.
中科院分区：
文献类型：
--
作者：
Bagnasco, L.;Tortolina, L.;Parodi, S.
c-Myc是一种转录调节原癌基因。当过表达时，它成为恶性转化多命中过程的重要贡献者。在该杂志之前的两篇论文中（见参考文献）。19,20)我们报道了由c-Myc基序的Helix-1激发的逆转录反肽模拟分子可能是在低微摩尔范围内具有活性的序列特异性抗增殖剂。我们还发现我们的肽没有打开4 - α螺旋Myc:Max束。它们在癌细胞系中的抗增殖活性需要在相应的原生H1基序的束外突出的侧链的存在。这一观察表明有外部伙伴的干扰。在这项研究中，我们研究了INI1:Myc的相互作用。INI1是SWI/SNF复合物（Myc:Max异源二聚体周围增强体的组成部分）的一个亚基。通过拉下、ELISA和荧光各向异性试验证实了INI1:Myc的相互作用。根据INI1片段的长度，我们计算出K(d)s的范围在1.3 x 10（-6）和4.8 x 10(-7) m之间。应用的三种不同技术表明，INI1:Myc相互作用也是我们的逆转录逆肽模拟分子的目标，这些分子似乎在INI1上特异性结合。一个Myc结合，21aa INI1片段（最小相互作用序列），可以激发合成一类新的更具选择性的c-Myc抑制剂。
c-Myc is a transcription modulator protooncogene. When overexpressed, it becomes an important contributor to the multi-hit process of malignant transformation. In two earlier papers in this journal (see refs. 19, 20) we reported that retro-inverso peptidomimetic molecules inspired by the Helix-1 of c-Myc motif could be sequence-specific antiproliferative agents active in the low micromolar range. We also found that our peptides were not opening the four-alpha-helix Myc:Max bundle. Their antiproliferative activity in cancer cell lines needs the presence of side chains projecting outside of the bundle in the corresponding native H1 motif. This observation suggested interference with an external partner. In this study we investigated the INI1:Myc interaction. INI1 is a subunit of the SWI/SNF complex (component of the enhanceosome surrounding Myc:Max heterodimer). The INI1:Myc interaction was confirmed via pull down, ELISA, and fluorescence anisotropy assays. According to the length of INI1 fragments used, we calculated K(d)s ranging between 1.3 x 10(-6) and 4.8 x 10(-7) M. The three different techniques applied showed that the INI1:Myc interaction was also the target of our retro-inverso peptidomimetic molecules, which seem to bind specifically at INI1. A Myc binding, 21aa INI1 fragment (minimum interacting sequence), could inspire the synthesis of a new class of more selective c-Myc inhibitors.