SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress
SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress
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DOI：
10.1038/sj.onc.1209857
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发表时间：
2007-02-01
期刊：
影响因子：
8
通讯作者：
Oshimura, M.
中科院分区：
文献类型：
--
作者：
Inoue, T.;Hiratsuka, M.;Oshimura, M.
我们之前发现SIRT2是一种烟酰胺腺嘌呤二核苷酸（NAD）依赖的微管蛋白去乙酰化酶，在胶质瘤和胶质瘤细胞系中是一种下调的蛋白，其特征是非整倍体。其他研究报道SIRT2参与正常细胞周期的有丝分裂进程。我们在此研究了SIRT2是否在有丝分裂检查点中起作用，以响应微管毒物引起的有丝分裂应激。通过监测染色体凝聚，发现外源表达的SIRT2在神经胶质瘤细胞系中阻断了染色体凝聚的进入和随后的超倍体细胞形成，并在有丝分裂应激下持续保持细胞周期蛋白B/cdc2活性。因此，SIRT2是一种新的有丝分裂检查点蛋白，在早期中期起作用，防止染色体不稳定（CIN），这是先前报道的CHFR蛋白的特征。我们进一步发现，组蛋白去乙酰化而非SIRT2 5'非翻译区异常DNA甲基化参与了SIRT2的下调。虽然SIRT2通常只位于细胞质中，但在正常人类中，用核输出抑制剂leptomycin B和电离辐射治疗后，观察到SIRT2在细胞核中的快速积累。表明核细胞质穿梭调节SIRT2功能。总之，我们的研究结果表明，进一步研究SIRT2可能为CIN、表观遗传调控和肿瘤发生之间的关系提供新的见解。
We previously identified SIRT2, an nicotinamide adenine dinucleotide (NAD)-dependent tubulin deacetylase, as a protein downregulated in gliomas and glioma cell lines, which are characterized by aneuploidy. Other studies reported SIRT2 to be involved in mitotic progression in the normal cell cycle. We herein investigated whether SIRT2 functions in the mitotic checkpoint in response to mitotic stress caused by microtubule poisons. By monitoring chromosome condensation, the exogenously expressed SIRT2 was found to block the entry to chromosome condensation and subsequent hyperploid cell formation in glioma cell lines with a persistence of the cyclin B/cdc2 activity in response to mitotic stress. SIRT2 is thus a novel mitotic checkpoint protein that functions in the early metaphase to prevent chromosomal instability (CIN), characteristics previously reported for the CHFR protein. We further found that histone deacetylation, but not the aberrant DNA methylation of SIRT2 5'untranslated region is involved in the downregulation of SIRT2. Although SIRT2 is normally exclusively located in the cytoplasm, the rapid accumulation of SIRT2 in the nucleus was observed after treatment with a nuclear export inhibitor, leptomycin B and ionizing radiation in normal human. fibroblasts, suggesting that nucleo-cytoplasmic shuttling regulates the SIRT2 function. Collectively, our results suggest that the further study of SIRT2 may thus provide new insights into the relationships among CIN, epigenetic regulation and tumorigenesis.