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Wen W Zhu F Zhang J Keum YS Zykova T Yao K Peng C Zheng D Cho YY Ma WY Bode AM Dong Z 《The Journal of biological chemistry》2010,285(50):39108-39116
MST1 (mammalian STE20-like kinase 1) is a serine/threonine kinase that is cleaved and activated by caspases during apoptosis. Overexpression of MST1 induces apoptotic morphological changes such as chromatin condensation, but the mechanism is not clear. Here we show that MST1 induces apoptotic chromatin condensation through its phosphorylation of histone H2AX at Ser-139. During etoposide-induced apoptosis in Jurkat cells, the cleavage of MST1 directly corresponded with strong H2AX phosphorylation. In vitro kinase assay results showed that MST1 strongly phosphorylates histone H2AX. Western blot and kinase assay results with a mutant S139A H2AX confirmed that MST1 phosphorylates H2AX at Ser-139. Direct binding of MST1 and H2AX can be detected when co-expressed in HEK293 cells and was also confirmed by an endogenous immunoprecipitation study. When overexpressed in HeLa cells, both the MST1 full-length protein and the MST1 kinase domain (MST1-NT), but not the kinase-negative mutant (MST1-NT-KN), could induce obvious endogenous histone H2AX phosphorylation. The caspase-3 inhibitor benzyloxycarbonyl-DEVD-fluoromethyl ketone (Z-DEVD-fmk) attenuates phosphorylation of H2AX by MST1 but cannot inhibit MST1-NT-induced histone H2AX phosphorylation, indicating that cleaved MST1 is responsible for H2AX phosphorylation during apoptosis. Histone H2AX phosphorylation and DNA fragmentation were suppressed in MST1 knockdown Jurkat cells after etoposide treatment. Taken together, our data indicated that H2AX is a substrate of MST1, which functions to induce apoptotic chromatin condensation and DNA fragmentation. 相似文献
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Detection of the synergetic effects between variants, such as single-nucleotide polymorphisms (SNPs), is crucial for understanding the genetic characters of complex diseases. Here, we proposed a two-step approach to detect differentially inherited SNP modules (synergetic SNP units) from a SNP network. First, SNP-SNP interactions are identified based on prior biological knowledge, such as their adjacency on the chromosome or degree of relatedness between the functional relationships of their genes. These interactions form SNP networks. Second, disease-risk SNP modules (or sub-networks) are prioritised by their differentially inherited properties in IBD (Identity by Descent) profiles of affected and unaffected sibpairs. The search process is driven by the disease information and follows the structure of a SNP network. Simulation studies have indicated that this approach achieves high accuracy and a low false-positive rate in the identification of known disease-susceptible SNPs. Applying this method to an alcoholism dataset, we found that flexible patterns of susceptible SNP combinations do play a role in complex diseases, and some known genes were detected through these risk SNP modules. One example is GRM7, a known alcoholism gene successfully detected by a SNP module comprised of two SNPs, but neither of the two SNPs was significantly associated with the disease in single-locus analysis. These identified genes are also enriched in some pathways associated with alcoholism, including the calcium signalling pathway, axon guidance and neuroactive ligand-receptor interaction. The integration of network biology and genetic analysis provides putative functional bridges between genetic variants and candidate genes or pathways, thereby providing new insight into the aetiology of complex diseases. 相似文献
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一氧化氮增加常氧和缺氧豚鼠心室肌细胞持续性钠电流 总被引:7,自引:1,他引:7
运用全细胞膜片钳记录缺氧条件下豚鼠心室肌持续性钠电流(INa.P)的变化及施加药物对其的影响,以探讨 INa.P 的本质及缺氧增大 INa.P 的机制。结果显示:(1)在常氧条件下,一氧化氮(NO)前体 L- 精氨酸(L-Arg)和供体硝普钠(SNP)浓度依赖性地增大INa.P; (2)INa.P 随缺氧时间延长而增大, 缺氧15 min 后施加 NO 合酶(NOS)抑制剂L- 硝基精氨酸甲酯(L-NAME), 不能使增大的INa.P 明显回复[(1.344 ±0.320) vs (1.301 ±0.317) pA/pF, P>0.05, n=5]; (3)缺氧时含L-NAME 的灌流液可使INa.P 明显减小,与单纯缺氧相比有显著差异[(0.914 ± 0.263), n=5 vs (1.344 ± 0.320) pA/pF, n=6, P<0.05], 但仍比常氧条件下增大[(0.914 ±0.263) vs (0.497 ±0.149) pA/pF, P<0.05, n=5]; (4)还原剂1,4-二硫代苏糖醇(DTT)不但可使L-Arg 及缺氧后施加SNP 增大的 INa.P 回复[(1.449 ± 0.522) vs (0.414 ± 0.067) pA/pF, P<0.01, n = 6 和(0.436 ± 0.141) vs (1.786 ± 0.636) pA/pF,P<0.01, n=5],而且使正常的 INa.P 减小[(0.396 ± 0.057) pA/pF vs (0.442 ± 0.056) pA/pF, P<0.01, n=6]。本实验结果表明缺氧可增大心室肌细胞的INa.P, 其作用机制可能是缺氧时心肌产生的NO 通过氧化细胞膜上钠通道蛋白所致,正常INa.P 的产生 相似文献
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Previous studies from this laboratory suggested that the periaqueductal gray (PAG), nucleus accumbens, and amygdala might take part in a serial, unidirectional mesolimbic loop to play their roles in pain modulation. It has been proposed that morphine injected into one of these nuclei would cause the release of opioid peptides in one nucleus after another. This working hypothesis was examined in the present study by perfusing simultaneously the PAG and the amygdala after microinjection of morphine into the N. accumbens. It was found that microinjection of morphine increased the content of immunoreactive enkephalins (ir-ENK) and immunoreactive beta-endorphin (ir-beta-EP) in the perfusate of the PAG and the amygdala. When the perfusion fluid contained 3 microM of naloxone, the increase of ir-ENK and ir-beta-EP was reduced significantly. These results indicate that the three nuclei were not serially connected in a unidirectional loop. 相似文献
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Five new guaiane sesquiterpenes, 1 – 5 , were isolated from the culture broth of the endophytic fungus Xylaria sp. YM 311647, isolated from Azadirachta indica A. Juss . The structures of these compounds were elucidated on the basis of spectroscopic analyses, and their inhibitory activities against five pathogenic fungi were evaluated. All guaiane sesquiterpenes showed moderate or weak antifungal activities in a broth microdilution assay. 相似文献