Ceramide synthases 2, 5, and 6 confer distinct roles in radiation-induced apoptosis in HeLa cells.
Ceramide synthases 2, 5, and 6 confer distinct roles in radiation-induced apoptosis in HeLa cells.
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DOI：
10.1016/j.cellsig.2010.04.006
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发表时间：
2010-09
影响因子：
4.8
通讯作者：
Kolesnick R
中科院分区：
文献类型：
--
作者：
Mesicek J;Lee H;Feldman T;Jiang X;Skobeleva A;Berdyshev EV;Haimovitz-Friedman A;Fuks Z;Kolesnick R
随着神经酰胺合成酶（CerS）的新作用和生化特性的研究进展，神经酰胺新生在细胞应激反应信号传导中的作用越来越受到关注。选择性组织和亚细胞分布的六种哺乳动物CerS亚型，结合不同的脂肪酰基链长底物的偏好，牵连细胞信号传导中的特定神经酰胺种类的差异功能。我们在这里报告，电离辐射（IR）诱导从头合成的神经酰胺，影响HeLa细胞凋亡，通过特异性激活CerS亚型2，5和6，产生相反的抗和促凋亡的神经酰胺在线粒体膜。CerS2的过表达导致部分保护IR诱导的凋亡，而CerS5的过表达增加HeLa细胞的凋亡。敲除研究确定CerS2负责所有可观察到的IR诱导的C24：0 CerS活性，而CerS5和CerS6各自赋予C16：0 CerS基线合成活性的约50%，两者都是IR诱导活性所需的。此外，免疫共沉淀研究表明，CerS2，5和6可能存在于HeLa细胞中的杂合物，提供了进一步的了解CerS蛋白的调节。这些数据增加了越来越多的证据表明CerS蛋白之间的相互作用，在一个应力刺激，细胞类型和亚细胞区室的具体方式。
The role of ceramide neo-genesis in cellular stress response signaling is gaining increasing attention with recent progress in elucidating the novel roles and biochemical properties of the ceramide synthase (CerS) enzymes. Selective tissue and subcellular distribution of the six mammalian CerS isoforms, combined with distinct fatty acyl chain length substrate preferences, implicate differential functions of specific ceramide species in cellular signaling. We report here that ionizing radiation (IR) induces de novo synthesis of ceramide to influence HeLa cell apoptosis by specifically activating CerS isoforms 2, 5, and 6 that generate opposing anti- and pro-apoptotic ceramides in mitochondrial membranes. Overexpression of CerS2 resulted in partial protection from IR-induced apoptosis whereas overexpression of CerS5 increased apoptosis in HeLa cells. Knockdown studies determined that CerS2 is responsible for all observable IR-induced C24:0 CerS activity, and while CerS5 and CerS6 each confer ∼50% of the C16:0 CerS baseline synthetic activity, both are required for IR-induced activity. Additionally, co-immunoprecipitation studies suggest that CerS2, 5, and 6 might exist as heterocomplexes in HeLa cells, providing further insight into regulation of CerS proteins. These data add to the growing body of evidence demonstrating interplay among the CerS proteins in a stress stimulus-, cell type- and subcellular compartment-specific manner.
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影响因子：
4.1
作者：
Mizutani, Y;Kihara, A;Igarashi, Y
通讯作者：
Igarashi, Y
影响因子：
4.8
作者：
Gao, ZH;Shao, YF;Jiang, XJ
通讯作者：
Jiang, XJ
影响因子：
4.8
作者：
Cremesti, A;Paris, F;Kolesnick, R
通讯作者：
Kolesnick, R
DOI：
10.1016/j.tripleo.2004.09.018
发表时间：
2005-09-01
期刊：
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTOLOGY
影响因子：
--
作者：
Hwang, D;Popat, R;Sonis, ST
通讯作者：
Sonis, ST
DOI：
10.1126/science.1158111
发表时间：
2008-10-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Deng X;Yin X;Allan R;Lu DD;Maurer CW;Haimovitz-Friedman A;Fuks Z;Shaham S;Kolesnick R
通讯作者：
Kolesnick R