Mizejewski G J
Division of Translational Medicine, Wadsworth Center, New York State Department of Health, PO Box 509, Empire State Plaza, Albany, NY, 12201-0509, USA.
Tumour Biol. 2016 Sep;37(9):12697-12711. doi: 10.1007/s13277-016-5131-x. Epub 2016 Jul 22.
The carboxy-terminal third domain of alpha-fetoprotein (AFP-3D) is known to harbor binding and/or interaction sites for hydrophobic ligands, receptors, and binding proteins. Such reports have established that AFP-3D consists of amino acid (AA) sequence stretches on the AFP polypeptide that engages in protein-to-protein interactions with various ligands and receptors. Using a computer software program specifically designed for such interactions, the present report identified AA sequence fragments on AFP-3D that could potentially interact with a variety of cell cycle proteins. The cell cycle proteins identified were (1) cyclins, (2) cyclin-dependent kinases, (3) cell cycle-associated proteins (inhibitors, checkpoints, initiators), and (4) ubiquitin ligases. Following detection of the AFP-3D to cell cycle protein interaction sites, the computer-derived AFP localization AA sequences were compared and aligned with previously reported hydrophobic ligand and receptor interaction sites on AFP-3D. A literature survey of the association of cell cycle proteins with AFP showed both positive relationships and correlations. Previous reports of experimental AFP-derived peptides effects on various cell cycle proteins served to confirm and verify the present computer cell cycle protein identifications. Cell cycle protein interactions with AFP-CD peptides have been reported in cultured MCF-7 breast cancer cells subjected to mRNA microarray analysis. After 7 days in culture with MCF-7 cells, the AFP-derived peptides were shown to downregulate cyclin E, SKP2, checkpoint suppressors, cyclin-dependent kinases, and ubiquitin ligases that modulate cyclin E/CdK2 transition from the G1 to the S-phase of the cell cycle. Thus, the experimental data on AFP-CD interaction with cell cycle proteins were consistent with the "in silico" findings.
众所周知，甲胎蛋白的羧基末端第三个结构域（AFP - 3D）含有与疏水配体、受体及结合蛋白的结合和/或相互作用位点。此类报告已证实，AFP - 3D由AFP多肽上的氨基酸（AA）序列片段组成，这些片段参与与各种配体和受体的蛋白质 - 蛋白质相互作用。本报告使用专门为此类相互作用设计的计算机软件程序，鉴定出AFP - 3D上可能与多种细胞周期蛋白相互作用的AA序列片段。鉴定出的细胞周期蛋白包括：（1）细胞周期蛋白；（2）细胞周期蛋白依赖性激酶；（3）细胞周期相关蛋白（抑制剂、检查点蛋白、起始蛋白）；（4）泛素连接酶。在检测到AFP - 3D与细胞周期蛋白的相互作用位点后，将计算机推导的AFP定位AA序列与先前报道的AFP - 3D上的疏水配体和受体相互作用位点进行比较和比对。对细胞周期蛋白与AFP关联的文献调查显示了正相关关系。先前关于AFP衍生肽对各种细胞周期蛋白影响的实验报告有助于证实和验证目前计算机对细胞周期蛋白的鉴定。在进行mRNA微阵列分析的培养MCF - 7乳腺癌细胞中，已报道了细胞周期蛋白与AFP - CD肽的相互作用。在用MCF - 7细胞培养7天后，AFP衍生肽显示出可下调细胞周期蛋白E、SKP2、检查点抑制因子、细胞周期蛋白依赖性激酶以及调节细胞周期从G1期到S期的细胞周期蛋白E/CdK2转变的泛素连接酶。因此，关于AFP - CD与细胞周期蛋白相互作用的实验数据与“计算机模拟”结果一致。
