Nahálková Jarmila
Biochemistry, Molecular, and Cell Biology Unit, Biochemworld co., Snickar-Anders väg 17, 74394, Skyttorp, Uppsala County, Sweden.
J Theor Biol. 2020 Feb 21;487:110124. doi: 10.1016/j.jtbi.2019.110124. Epub 2019 Dec 18.
PIN7 is a protein-protein interaction network of seven pleiotropic proteins (TPPII, CDK2, MYBBP1A, p53, SIRT6, SIRT7, and CD147) with proposed multiple functions in the aging and age-related diseases including cancer and neurodegeneration. Since the animal and cellular models with downregulated or knockout TPPII, p53, SIRT6, SIRT7, and MYBBP1A expression levels demonstrate similar age-related phenotype features, the interaction network was subjected to further investigation. For the identification of the main molecular mechanisms enabling the functions of the interaction network, PIN7 was subjected to the pathway enrichment, protein function prediction, and the protein node prioritization analysis using Cytoscape software and its applications GeneMania, ClusterOne, and Cyto-hubba. The study identified the p53 signaling pathway as the most dominant mediator of PIN7 effect. The top-ranked protein nodes of PIN7 extended by GeneMania application belong to the group of histone acetyltransferases and histone deacetylases. These enzymes are involved in the reverse epigenetic regulation mechanisms linked to the regulation of PTK2, NFκB, and p53 signaling interaction subnetworks of the extended PIN7. The analysis emphasized the role of PTK2 signaling, which functions upstream of the p53 signaling pathway, and its interaction network includes all top rank protein nodes of the extended PIN7 and all members of the sirtuin family (SIRT1-SIRT7). Further, the analysis suggests the involvement of molecular mechanisms related to metastatic cancer (prostate cancer, small cell lung cancer), hemostasis, the regulation of the thyroid hormones, and the cell cycle G1/S checkpoint. The additional data-mining analysis shows that the protein interaction network MYBBP1A-p53-TPPII-SIRT6-CD147 controls the Warburg effect, and MYBBP1A-p53-TPPII-SIRT7-CD147 influences mTOR signaling and autophagy. The proposed insights into the molecular mechanisms of aging and age-related diseases could be valuable for the discovery of new controlling interaction clusters, which could contribute to the development of the multitarget therapeutical strategies.
PIN7是一个由七种多效性蛋白质（TPPII、CDK2、MYBBP1A、p53、SIRT6、SIRT7和CD147）组成的蛋白质-蛋白质相互作用网络，在衰老及包括癌症和神经退行性疾病在内的与年龄相关的疾病中具有多种功能。由于下调或敲除TPPII、p53、SIRT6、SIRT7和MYBBP1A表达水平的动物和细胞模型表现出相似的与年龄相关的表型特征，因此对该相互作用网络进行了进一步研究。为了确定使该相互作用网络发挥功能的主要分子机制，使用Cytoscape软件及其应用程序GeneMania、ClusterOne和Cyto-hubba对PIN7进行了通路富集、蛋白质功能预测和蛋白质节点优先级分析。该研究确定p53信号通路是PIN7效应最主要的介导因子。通过GeneMania应用程序扩展的PIN7的排名靠前的蛋白质节点属于组蛋白乙酰转移酶和组蛋白去乙酰化酶类别。这些酶参与与扩展PIN7的PTK2、NFκB和p53信号相互作用子网调控相关的反向表观遗传调控机制。该分析强调了PTK2信号传导的作用，其在p53信号通路的上游发挥作用，并且其相互作用网络包括扩展PIN7的所有排名靠前的蛋白质节点和沉默调节蛋白家族（SIRT1-SIRT7）的所有成员。此外，该分析表明与转移性癌症（前列腺癌、小细胞肺癌）、止血、甲状腺激素调节和细胞周期G1/S检查点相关的分子机制也参与其中。额外的数据挖掘分析表明，蛋白质相互作用网络MYBBP1A-p53-TPPII-SIRT6-CD147控制瓦伯格效应，而MYBBP1A-p53-TPPII-SIRT7-CD则影响mTOR信号传导和自噬。对衰老及与年龄相关疾病分子机制的这些见解可能对发现新的控制相互作用簇很有价值，这可能有助于多靶点治疗策略的开发。
