Department of Biophysics, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata, West Bengal.
Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata, West Bengal.
J Biochem. 2019 Nov 1;166(5):403-413. doi: 10.1093/jb/mvz050.
Human positive coactivator 4 (PC4), a multifunctional chromatin-associated protein, is known to directly interact with p53 and modulate expressions of a few p53-dependent genes. However, the role of PC4 in p53's myriad of other regulatory functions is not known. The p53-PC4 interaction was selectively perturbed by a small peptide which led to abrogation of genotoxic stress-induced up-regulation of many p53-dependent genes and reduction of apoptosis in A549 cells. Over-expression of a PC4 point mutant, incapable of binding p53, recapitulated many of the effects of the peptide. Global gene expression profiling in A549 cells, upon peptide treatment, revealed PC4's involvement in the regulation of many p53-dependent pathways, including the Hippo pathway. Introduction of the peptide in neuronal cells significantly reduced its amyloid-β-induced death. Thus, PC4 emerges as a global co-regulator of p53 and a therapeutic target against pathogeneses where the p53-dependent cell death process plays a crucial role.
人类阳性共激活因子 4（PC4）是一种多功能染色质相关蛋白，已知可直接与 p53 相互作用，并调节少数几个 p53 依赖性基因的表达。然而，PC4 在 p53 众多其他调节功能中的作用尚不清楚。一种小肽选择性地扰乱了 p53-PC4 相互作用，导致许多 p53 依赖性基因在遗传毒性应激诱导下的上调和 A549 细胞凋亡减少。不能结合 p53 的 PC4 点突变体的过表达，重现了该肽的许多作用。在 A549 细胞中用肽处理后的全基因表达谱分析表明，PC4 参与了许多 p53 依赖性途径的调节，包括 Hippo 途径。在神经元细胞中引入该肽可显著降低其淀粉样β诱导的死亡。因此，PC4 作为 p53 的全局共调节剂出现，并成为治疗那些依赖 p53 的细胞死亡过程发挥关键作用的疾病的治疗靶点。
