Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond-Blackfan anemia.
Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond-Blackfan anemia.
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DOI：
10.1016/j.bbadis.2009.08.002
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发表时间：
2009-10
影响因子：
6.2
通讯作者：
Dahl, Niklas
中科院分区：
文献类型：
--
作者：
Badhai, Jitendra;Frojmark, Anne-Sophie;Davey, Edward J.;Schuster, Jens;Dahl, Niklas
Diamond-Blackfan贫血（DBA）是一种严重的先天性贫血，其特征是红系前体细胞减少。该疾病还与生长迟缓、先天性畸形、恶性疾病的易感性和核糖体蛋白（RP）基因RPS7、RPS17、RPS19、RPS24、RPL 5、RPL 11和RPL 35 a中任一个的杂合突变相关。我们在此表明，在RPS19或RPS24中具有截短突变的DBA患者的原代成纤维细胞的增殖能力显著降低。当与w.t.相比时，突变成纤维细胞与延长的细胞周期和正常的p53水平相关。细胞RPS19突变成纤维细胞在G1期积累，而RPS24突变细胞在S期显示出改变的进展，导致G2/M期水平降低。RPS19缺陷型细胞表现出细胞周期蛋白-E、CDK2和视网膜母细胞瘤（Rb）蛋白水平降低，支持细胞周期停滞在G1期。相比之下，RPS24缺陷型细胞显示细胞周期抑制剂p21的水平增加，并且细胞周期蛋白-E、CDK4和CDK6似乎相反地增加。结合起来，我们的结果表明，RPS19和RPS24不足的成纤维细胞具有由细胞周期中的不同阻滞引起的受损的生长。我们认为，这种增殖约束是一个重要的贡献机制，在DBA中观察到的复杂的血液学特征。
Diamond-Blackfan anemia (DBA) is a severe congenital anemia characterized by a specific decrease of erythroid precursors. The disease is also associated with growth retardation, congenital malformations, a predisposition for malignant disease and heterozygous mutations in either of the ribosomal protein (RP) genes RPS7, RPS17, RPS19, RPS24, RPL5, RPL11 and RPL35a. We show herein that primary fibroblast from DBA patients with truncating mutations in RPS19 or in RPS24 have a marked reduction in proliferative capacity. Mutant fibroblasts are associated with extended cell cycles and normal levels of p53 when compared to w.t. cells. RPS19 mutant fibroblasts accumulate in the G1 phase, whereas the RPS24 mutant cells show an altered progression in the S phase resulting in reduced levels in the G2/M phase. RPS19 deficient cells exhibit reduced levels of Cyclin-E, CDK2 and retinoblastoma (Rb) protein supporting a cell cycle arrest in the G1 phase. In contrast, RPS24 deficient cells show increased levels of the cell cycle inhibitor p21 and a seemingly opposing increase in Cyclin-E, CDK4 and CDK6. In combination, our results show that RPS19 and RPS24 insufficient fibroblasts have an impaired growth caused by distinct blockages in the cell cycle. We suggest this proliferative constraint to be an important contributing mechanism for the complex extra-hematological features observed in DBA.
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