舒瓦赫曼-博迪恩-钻石综合征基因 258+2T > C 突变导致舒瓦赫曼-博迪恩-钻石综合征细胞模型出现有丝分裂异常和纺锤体组装检查点失活。

IF 1.9 Q3 PHARMACOLOGY & PHARMACY Drug Discoveries and Therapeutics Pub Date : 2024-11-15 Epub Date: 2024-10-26 DOI:10.5582/ddt.2024.01070
Yukihiro Sera, Tsuneo Imanaka, Yusuke Iguchi, Masafumi Yamaguchi
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引用次数: 0

摘要

血液学异常是舒瓦赫曼-钻石综合征(SDS)最常见的症状。SDS 的致病基因是 Shwachman-Bodian-Diamond 综合征(SBDS)基因;然而,SBDS 的功能和 SDS 中每种病症的发病机理在很大程度上都是未知的。已知 SBDS 定位于有丝分裂轴并稳定微管。此前,我们证明了 SBDS 在有丝分裂期被泛素化并随后降解,从而加速了有丝分裂的进程。在这项研究中,我们研究了 SDS 骨髓细胞模型(SDS 细胞)中的有丝分裂。对诺贺唑同步化细胞进行4',6-二脒基-2-苯基吲哚(DAPI)染色的染色体观察和细胞周期分析发现,SDS细胞的有丝分裂异常迅速。此外,还检测到许多滞后染色体和微核。此外,苏氨酸酪氨酸激酶(纺锤体组装检查点(SAC)的关键激酶)的磷酸化受到抑制。SAC功能障碍导致的染色体不稳定性可能引发多种临床症状,包括SDS患者的血液肿瘤。
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Mitotic abnormalities and spindle assembly checkpoint inactivation in a cell model of Shwachman-Diamond syndrome with mutations in the Shwachman-Bodian-Diamond syndrome gene, 258+2T > C.

Hematologic abnormalities are the most common symptoms of Shwachman-Diamond syndrome (SDS). The causative gene for SDS is the Shwachman-Bodian-Diamond syndrome (SBDS) gene; however, the function of SBDS and pathogenesis of each condition in SDS are largely unknown. SBDS is known to be localized at mitotic spindles and stabilizes microtubules. Previously, we demonstrated that SBDS is ubiquitinated and subsequently degraded in the mitotic phase, thereby accelerating mitotic progression. In this study, we examined mitosis in a myeloid cell model of SDS (SDS cells). 4',6-Diamidino-2-phenylindole (DAPI)-stained chromosome observation and cell cycle analysis of nocodazole-synchronized cells revealed that the SDS cells have abnormally rapid mitosis. In addition, many lagging chromosomes and micronuclei were detected. Moreover, the phosphorylation of threonine tyrosine kinase, the crucial kinase of the spindle assembly checkpoint (SAC), was suppressed. Chromosomal instability caused by SAC dysfunction may cause a variety of clinical conditions, including hematologic tumors in patients with SDS.

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来源期刊
Drug Discoveries and Therapeutics
Drug Discoveries and Therapeutics PHARMACOLOGY & PHARMACY-
CiteScore
3.20
自引率
3.20%
发文量
51
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