SBDS-deficiency results in specific hypersensitivity to Fas stimulation and accumulation of Fas at the plasma membrane
SBDS-deficiency results in specific hypersensitivity to Fas stimulation and accumulation of Fas at the plasma membrane
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SBDS 缺乏会导致对 Fas 刺激的特异性超敏反应以及 Fas 在质膜上的积累
DOI：
10.1007/s10495-008-0275-9
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发表时间：
2009
期刊：
影响因子：
7.2
通讯作者：
et al
中科院分区：
文献类型：
--
作者：
Watanabe K;Ambekar C;Wang H;et al
Shwachman-Diamond综合征（SDS）是一种以骨髓和胰腺外分泌细胞减少为特征的遗传性疾病。大多数患者的SBDS基因发生突变，其功能尚不清楚。我们以前的研究表明，SBDS蛋白缺陷的细胞的特点是加速凋亡和Fas超敏反应，这表明该蛋白可能在Fas介导的凋亡中发挥重要作用。为了研究Fas超敏性的机制，我们比较了shRNA介导的SBDS-敲低的HeLa细胞和SDS骨髓CD 34+细胞对几组凋亡诱导剂的敏感性。对Fas刺激有明显的超敏反应，但对肿瘤坏死因子-α、DNA损伤剂、转录抑制或蛋白质合成抑制无反应。为了鉴定引起超敏反应的Fas信号传导因子，我们分析了该途径蛋白的表达。我们发现在SBDS敲低的细胞中，Fas聚集在质膜上，并相应地表达Fas转录本1，其主要转录本包含跨膜结构域和死亡结构域。然而，Fas蛋白和mRNA的总水平与对照组相当，Fas内化正常发生。FADD、caspase-8和-3的表达没有升高，并且通路抑制剂：ERK、c-FLIP和XIAP没有降低。这些结果表明，SBDS损失导致Fas在质膜上的异常积累，在那里它使细胞对Fas配体的刺激敏感。
Shwachman–Diamond syndrome (SDS) is an inherited disorder characterized by reduced cellularity in the bone marrow and exocrine pancreas. Most patients have mutations in theSBDSgene, whose functions are unknown. We previously showed that cells deficient in the SBDS protein are characterized by accelerated apoptosis and Fas hypersensitivity, suggesting that the protein might play an important role in Fas-mediated apoptosis. To study the mechanism of Fas hypersensitivity, we compared shRNA-mediatedSBDS-knockdown HeLa cells and SDS marrow CD34+ cells for their sensitivity to several groups of apoptosis inducers. Marked hypersensitivity was noticed in response to Fas stimulation, but not to tumor necrosis factor-α, DNA-damaging agents, transcription inhibition or protein synthesis inhibition. To identify the Fas signaling factors that cause hypersensitivity, we analyzed the expression of the pathway’s proteins. We found that Fas accumulated at the plasma membrane inSBDS-knockdown cells with corresponding expression of Fas transcript 1, the main Fas transcript which contains both the transmembrane domain and the death domain. However, the total levels of Fas protein and mRNA were comparable to controls, and Fas internalization occurred normally. Expression of FADD, caspase-8 and -3 were not elevated and the pathway inhibitors: ERK, c-FLIP and XIAP were not decreased. These results suggest that SBDS loss results in abnormal accumulation of Fas at the plasma membrane, where it sensitizes the cells to stimulation by Fas ligand.
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一名患有 Shwachman-Diamond 综合征和严重骨髓衰竭的 10 岁男孩因环磷酰胺诱发致命性充血性心力衰竭，接受同种异体骨髓移植治疗。
DOI：
10.1097/00043426-199024000-00012
发表时间：
1990
期刊：
The American journal of pediatric hematology/oncology
影响因子：
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作者：
Tsai,PH;Sahdev,I;Herry,A;Lipton,JM
通讯作者：
Lipton,JM
Fas/APO-1 (CD95) 在骨髓增生异常综合征中的表达。
影响因子：
2.6
作者：
P. Lepelley;N. Grardel;O. Erny;T. Iaru;V. Obein;A. Cosson;P. Fenaux
通讯作者：
P. Fenaux
RNAi 调节基因表达。
DOI：
--
发表时间：
2005
期刊：
Methods in Molecular Medicine
影响因子：
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作者：
C. Wójcik;R. Fabunmi;G. Demartino
通讯作者：
G. Demartino
骨髓移植治疗Shwachman-Diamond综合征二例报告及文献复习
影响因子：
4.8
作者：
F. Okcu;W. Roberts;Kw Chan
通讯作者：
Kw Chan