Ribosomal protein L23 negatively regulates cellular apoptosis via the RPL23/Miz-1/c-Myc circuit in higher-risk myelodysplastic syndrome.
Ribosomal protein L23 negatively regulates cellular apoptosis via the RPL23/Miz-1/c-Myc circuit in higher-risk myelodysplastic syndrome.
复制标题
核糖体蛋白 L23 通过 RPL23/Miz-1/c-Myc 回路负向调节高危骨髓增生异常综合征中的细胞凋亡
DOI：
10.1038/s41598-017-02403-x
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发表时间：
2017-05-24
影响因子：
4.6
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Qi Y;Li X;Chang C;Xu F;He Q;Zhao Y;Wu L
核糖体蛋白 (RP) L23 是细胞凋亡的负调节因子，RPL23 过度表达与高危骨髓增生异常综合征 (MDS) 患者来源的 CD34+ 细胞的异常凋亡抵抗相关。然而，RPL23 在高危 MDS 患者中诱导细胞凋亡抵抗的机制尚不清楚。在这项研究中，我们发现 RPL23 表达减少会导致细胞活力抑制、细胞凋亡增加和 G1-S 细胞周期停滞。比较 RPL23 敲低细胞和对照细胞的基因微阵列分析发现了一系列差异表达基因，其中 Miz-1 通过细胞周期抑制剂 p15Ink4band p21Cip1 的反式激活而上调，而 Miz-1 的功能阻遏物 c-Myc 则下调。与来自低风险患者的细胞相比，来自高风险 MDS 患者的细胞表现出 RPL23 和 c-Myc 表达持续增加，而 Miz-1 表达减少。总之，在 RPL23 表达升高的情况下，Miz-1 依赖性的 p15Ink4band p21Cip1 诱导随着 Miz-1 的减少和 c-Myc 表达的增加而受到抑制，从而导致高危 MDS 患者出现细胞凋亡抵抗。由于 RPL23 是由 c-Myc 靶基因编码的，因此 RPL23/Miz-1/c-Myc 调节回路提供了一个反馈环，将 RPL23 的有效表达与 c-Myc 抑制 Miz-1 诱导的 Cdk 抑制剂的功能联系起来，从而导致高危 MDS 患者出现细胞凋亡抵抗。
Ribosomal protein (RP) L23 is a negative regulator of cellular apoptosis, and RPL23 overexpression is associated with abnormal apoptotic resistance in CD34+ cells derived from patients with higher-risk myelodysplastic syndrome (MDS). However, the mechanism underlying RPL23-induced apoptotic resistance in higher-risk MDS patients is poorly understood. In this study, we showed that reduced RPL23 expression led to suppressed cellular viability, increased apoptosis and G1-S cell cycle arrest. Gene microarray analysis comparing RPL23-knockdown and control cells identified an array of differentially expressed genes, of which, Miz-1, was upregulated with transactivation of the cell cycle inhibitors p15Ink4band p21Cip1, and Miz-1’s functional repressor, c-Myc, was downregulated. Cells derived from higher-risk MDS patients demonstrated consistently increased expression of RPL23 and c-Myc and decreased Miz-1 expression compared with cells from lower-risk patients. In conclusion, Miz-1-dependent induction of p15Ink4band p21Cip1was depressed with decreased Miz-1 and increased c-Myc expression under conditions of elevated RPL23 expression, leading to apoptotic resistance in higher-risk MDS patients. Because RPL23 is encoded by a target gene of c-Myc, the RPL23/Miz-1/c-Myc regulatory circuit provides a feedback loop that links efficient RPL23 expression with c-Myc’s function to suppress Miz-1-induced Cdk inhibitors and thereby leads to apoptotic resistance in higher-risk MDS patients.