转录因子（TF）是多种疾病的有前景的治疗靶点。转录因子通过参与多种特定的蛋白质-蛋白质相互作用来发挥其细胞作用。例如，一些 TF 的同二聚或异二聚化控制 DNA 结合，而 TF 与基础转录机制或染色质修饰剂成分之间的相互作用也可能至关重要。虽然从理论上讲，小分子可用于破坏 TF 功能所需的特定蛋白质-蛋白质界面，但在实践中，很难识别具有必要特异性和功效的小分子，这可能是由于广泛的蛋白质-蛋白质界面经常存在TF 功能的基础。然而，与小分子相比，肽有潜力提供破坏此类界面所需的特异性和功效。在这里，我们通过对源自人类核定位蛋白的 80 聚体蛋白区域（肽）文库进行高通量筛选，鉴定出~15 种抑制白血病细胞增殖的肽。抗增殖肽富集已知参与特定 TF 二聚化的区域，包括基本亮氨酸拉链 (bZIP) 结构域家族。这些 bZIP 结构域之一 JDP2；bZIP_1（来自 TF JDP2）是最重要的抗增殖肽，可将 K562 细胞的增殖减少 2 倍。 JDP2;bZIP_1 抑制 AP-1 转录活性并模仿 JDP2 过表达，表明该肽通过天然 JDP2 机制影响增殖。出乎意料的是，鉴于 bZIP 结构域的高度保守性，注释的二聚化结构域之外的残基对于肽的抗增殖效力至关重要。肽介导的抗增殖作用启动了 K562 细胞中的红细胞分化，并在多种细胞系模型中增加了 G0/G1 细胞。我们还发现，本研究中鉴定的许多抗增殖肽，包括 JDP2;bZIP_1，不需要核定位信号即可发挥作用，这是在治疗应用中传递这些肽的潜在好处。

Transcription factors (TFs) are a promising therapeutic target for a multitude of diseases. TFs perform their cellular roles by participating in multiple specific protein-protein interactions. For example, homo- or heterodimerization of some TFs controls DNA binding, while interactions between TFs and components of basal transcriptional machinery or chromatin modifiers can also be critical. While, in theory, small molecules could be used to disrupt specific protein-protein interfaces required for TF function, in practice, it is difficult to identify small molecules with the necessary specificity and efficacy, likely due to the extensive protein-protein interfaces that often underlie TF function. However, in contrast to small molecules, peptides have the potential to provide both the specificity and efficacy required to disrupt such interfaces. Here, we identified ∼15 peptides that inhibit the proliferation of leukemia cells using a high-throughput pooled screen of a library of 80-mer protein regions (peptides) derived from human nuclear-localized proteins. The antiproliferative peptides were enriched for regions known to be involved in specific TF dimerization, including the basic leucine zipper (bZIP) domain family. One of these bZIP domains, JDP2;bZIP_1, from the TF JDP2, was the top antiproliferative peptide, reducing the proliferation of K562 cells by 2-fold. JDP2;bZIP_1 inhibited AP-1 transcriptional activity and phenocopied JDP2 overexpression, suggesting that the peptide affected proliferation through a native JDP2 mechanism. Unexpectedly, given the strong conservation of the bZIP domain, residues outside of the annotated dimerization domain were critical for the peptide's antiproliferative potency. The peptide-mediated antiproliferative effect initiated erythrocyte differentiation in K562 cells and increased G0/G1 cells across multiple cell line models. We also found that many of the antiproliferative peptides identified in this study, including JDP2;bZIP_1, did not require a nuclear localization signal to function, a potential benefit for delivering these peptides in therapeutic applications.