Department of Laboratory Medicine, Translational Cancer Research, Lund University, Medicon Village, Lund, Sweden.
Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, USA.
Cell Death Dis. 2018 May 1;9(5):458. doi: 10.1038/s41419-018-0500-6.
BRCA1-associated protein 1 (BAP1) is a nuclear deubiquitinating enzyme that is associated with multiprotein complexes that regulate key cellular pathways, including cell cycle, cellular differentiation, cell death, and the DNA damage response. In this study, we found that the reduced expression of BAP1 pro6motes the survival of neuroblastoma cells, and restoring the levels of BAP1 in these cells facilitated a delay in S and G2/M phase of the cell cycle, as well as cell apoptosis. The mechanism that BAP1 induces cell death is mediated via an interaction with 14-3-3 protein. The association between BAP1 and 14-3-3 protein releases the apoptotic inducer protein Bax from 14-3-3 and promotes cell death through the intrinsic apoptosis pathway. Xenograft studies confirmed that the expression of BAP1 reduces tumor growth and progression in vivo by lowering the levels of pro-survival factors such as Bcl-2, which in turn diminish the survival potential of the tumor cells. Patient data analyses confirmed the finding that the high-BAP1 mRNA expression correlates with a better clinical outcome. In summary, our study uncovers a new mechanism for BAP1 in the regulation of cell apoptosis in neuroblastoma cells.
BRCA1 相关蛋白 1（BAP1）是一种核去泛素化酶，与调节细胞周期、细胞分化、细胞死亡和 DNA 损伤反应等关键细胞通路的多蛋白复合物相关联。在这项研究中，我们发现 BAP1 pro 表达降低促进神经母细胞瘤细胞的存活，而在这些细胞中恢复 BAP1 的水平则有利于细胞周期 S 和 G2/M 期的延迟以及细胞凋亡。BAP1 诱导细胞死亡的机制是通过与 14-3-3 蛋白相互作用介导的。BAP1 与 14-3-3 蛋白的结合将凋亡诱导蛋白 Bax 从 14-3-3 中释放出来，并通过内在凋亡途径促进细胞死亡。异种移植研究证实，BAP1 的表达通过降低生存因子（如 Bcl-2）的水平，从而降低肿瘤细胞的生存潜力，从而降低体内肿瘤的生长和进展。患者数据分析证实了 BAP1 mRNA 高表达与较好的临床结果相关的发现。总之，我们的研究揭示了 BAP1 在神经母细胞瘤细胞凋亡调节中的新机制。
