Laboratory of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima, Japan.
Drug Discov Ther. 2024 Nov 15;18(5):283-289. doi: 10.5582/ddt.2024.01070. Epub 2024 Oct 26.
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.
血液学异常是 Shwachman-Diamond 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 的功能以及 SDS 中每种病症的发病机制在很大程度上尚不清楚。已知 SBDS 定位于有丝分裂纺锤体，并稳定微管。此前，我们证明 SBDS 在有丝分裂期被泛素化并随后降解，从而加速有丝分裂进程。在这项研究中，我们在 SDS 的髓系细胞模型（SDS 细胞）中检查了有丝分裂。用 4'，6-二脒基-2-苯基吲哚（DAPI）染色染色体观察和长春花碱同步化细胞的细胞周期分析表明，SDS 细胞的有丝分裂异常迅速。此外，检测到许多滞后染色体和微核。此外，纺锤体组装检查点（SAC）的关键激酶苏氨酸酪氨酸激酶的磷酸化受到抑制。SAC 功能障碍引起的染色体不稳定可能导致各种临床病症，包括 SDS 患者的血液学肿瘤。
