Faculty of Pharmaceutical Science at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki 769-2193, Japan.
Faculty of Science and Engineering, Tokushima Bunri University, 1314-1 Shido, Sanuki 769-2193, Japan.
Biomolecules. 2024 Jul 23;14(8):885. doi: 10.3390/biom14080885.
Mouse double minute 2 (MDM2) is an oncoprotein that is frequently overexpressed in tumors and enhances cellular transformation. Owing to the important role of MDM2 in modulating p53 function, it is crucial to understand the mechanism underlying the regulation of MDM2 levels. We identified ribosomal protein S4X-linked (RPS4X) as a novel binding partner of MDM2 and showed that RPS4X promotes MDM2 stability. RPS4X suppressed polyubiquitination of MDM2 by suppressing homodimer formation and preventing auto-ubiquitination. Moreover, RPS4X inhibited the interaction between MDM2 and Cullin1, a scaffold protein of the Skp1-Cullin1-F-box protein (SCF) complex and an E3 ubiquitin ligase for MDM2. RPS4X expression in cells enhanced the steady-state level of MDM2 protein. RPS4X was associated not only with MDM2 but also with Cullin1 and then blocked the MDM2/Cullin1 interaction. This is the first report of an interaction between ribosomal proteins (RPs) and Cullin1. Our results contribute to the elucidation of the MDM2 stabilization mechanism in cancer cells, expanding our understanding of the new functions of RPs.
鼠双微体 2（MDM2）是一种癌蛋白，在肿瘤中经常过表达，并增强细胞转化。由于 MDM2 在调节 p53 功能方面的重要作用，因此了解调节 MDM2 水平的机制至关重要。我们鉴定出核糖体蛋白 S4X 连接物（RPS4X）是 MDM2 的一种新结合伴侣，并表明 RPS4X 可促进 MDM2 的稳定性。RPS4X 通过抑制同源二聚体形成和防止自身泛素化来抑制 MDM2 的多泛素化。此外，RPS4X 抑制了 MDM2 与 Cullin1 之间的相互作用，Cullin1 是 Skp1-Cullin1-F-box 蛋白（SCF）复合物和 MDM2 的 E3 泛素连接酶的支架蛋白。细胞中 RPS4X 的表达增强了 MDM2 蛋白的稳态水平。RPS4X 不仅与 MDM2 相关，而且与 Cullin1 相关，然后阻止了 MDM2/Cullin1 相互作用。这是核糖体蛋白（RPs）与 Cullin1 之间相互作用的首次报道。我们的研究结果有助于阐明癌细胞中 MDM2 稳定化的机制，扩展了对 RPs 新功能的理解。
