The c-Jun N-terminal kinase-associated leucine zipper protein (JLP), a scaffold protein of mitogen-activated protein kinase signaling pathways, is a multifunctional protein involved in a variety of cellular processes. It has been reported that JLP is overexpressed in various types of cancer and is expected to be a potential therapeutic target. However, whether and how JLP overexpression affects non-transformed cells remain unknown. Here, we aimed to investigate the effect of JLP overexpression on chromosomal stability in human non-transformed cells and the mechanisms involved. We found that aneuploidy was induced in JLP-overexpressed cells. Moreover, we established JLP-inducible cell lines and observed an increased frequency of chromosome missegregation, reduced time from nuclear envelope breakdown to anaphase onset, and decreased levels of the spindle assembly checkpoint (SAC) components at the prometaphase kinetochore in cells overexpressing the wild-type JLP. In contrast, we observed that a point mutant JLP lacking the ability to interact with dynein light intermediate chain 1 (DLIC1) failed to induce chromosomal instability. Our results suggest that overexpression of the wild-type JLP facilitates premature SAC silencing through interaction with DLIC1, leading to aneuploidy. This study provides a novel insight into the mechanism through which JLP overexpression is associated with cancer development and progression.

中文翻译：

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JNK 相关亮氨酸拉链蛋白的过度表达通过与动力蛋白轻中间链 1 相互作用诱导染色体不稳定

c-Jun N 端激酶相关亮氨酸拉链蛋白 (JLP) 是丝裂原激活蛋白激酶信号通路的支架蛋白，是一种参与多种细胞过程的多功能蛋白。据报道，JLP在多种类型的癌症中过度表达，有望成为潜在的治疗靶点。然而，JLP 过度表达是否以及如何影响非转化细胞仍不清楚。在这里，我们的目的是研究JLP过表达对人类非转化细胞染色体稳定性的影响及其机制。我们发现 JLP 过表达的细胞中诱导了非整倍性。此外，我们建立了 JLP 诱导细胞系，并观察到过表达野生型的细胞中染色体错误分离频率增加，从核膜破裂到后期开始的时间缩短，以及中期着丝粒纺锤体组装检查点 (SAC) 成分的水平降低。类型 JLP。相反，我们观察到缺乏与动力蛋白轻中间链 1 (DLIC1) 相互作用的能力的点突变 JLP 未能诱导染色体不稳定。我们的结果表明，野生型 JLP 的过度表达通过与 DLIC1 相互作用促进 SAC 过早沉默，从而导致非整倍性。这项研究为 JLP 过度表达与癌症发生和进展相关的机制提供了新的见解。