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51.
Switch in Fas-activated death signaling pathway as result of keratin 8/18-intermediate filament loss
Stéphane Gilbert Alexandre Ruel Anne Loranger Normand Marceau 《Apoptosis : an international journal on programmed cell death》2008,13(12):1479-1493
Fas-induced apoptosis is initiated through the recruitment of FADD and procaspase 8 to form the death-inducing signaling complex
(DISC). In some cells (type I cells) the initiator caspase 8 directly activates effector caspases such as procaspase 3, whereas
in others (type II cells) the death signal is amplified through mitochondria. In epithelial cells, Fas-induced hierarchic
caspase activation is also linked with DEDD, a member of the DED family that binds to keratin (K) intermediate filaments (IFs).
Hepatocytes are type II cells and their IFs are made exclusively of K8/K18. We have shown previously that K8-null mouse hepatocytes,
lacking K8/K18 IFs, are more sensitive than their wild-type counterparts to Fas-induced apoptosis. Here, by examining the
cell-death kinetics and death-signaling ordering, we found that K8-null hepatocytes exhibited prominent DISC formation, higher
procaspase 8 activation and direct procaspase 3 activation as reported for type I cells; however they experienced a reduced
Bid cleavage and a stronger procaspase 9 activation. In addition, the K8/K18 loss altered the DEDD ubiquitination status and
nuclear/cytoplasmic distribution. Together, the results suggest that the K8/K18 loss induces a switch in Fas-induced death
signaling, likely through a DEDD involvement.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
52.
FasL/Fas系统介导的胞外信号凋亡途径是哺乳动物睾丸生殖细胞凋亡的一条主要途径,然而,关于FasL在睾丸细胞中的定位却存在争议。本文对近年来国内外关于FasL在睾丸中的细胞定位研究进行了综述,为阐明FasL/Fas系统介导生殖细胞凋亡的机制提供资料,对深入理解睾丸中Sertoli细胞和生殖细胞间的调控关系及临床实践具有一定的指导作用。 相似文献
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Using immunohistochemistry, in situ hybridization, Western blot and TUNEL methods, we have studied the expression of Fas/FasL, Bcl-2/Bax and caspase-3 in the
corpora lutea (CL) at various stages of pseudopregnant rat induced by injection of PMSF/hCG. The results showed that no apoptotic
signal could be observed until Day 14 after hCG injection. Fas weakly expressed in the CL at all the stages increased when
luteolysis took place. FasL signal increased dramatically on Day 14 and reached the maximum level on Day 21. The expression
of Bcl-2 and Bax was detected in a time-dependent manner. At the early stage of CL development, Bcl-2 expression was stronger,
while Bax was low. The expression of Bcl-2 and Bax in the CL was completely reversed. Caspase-3 antigen could be detected
throughout all the phases of CL development in a time-dependent fashion, low on Day 2 and reaching the maximum on Day 21.
These results suggest that luteal regression at the late phases may be related to cell apoptosis. 相似文献
56.
Lee JK Sayers TJ Back TC Wigginton JM Wiltrout RH 《Apoptosis : an international journal on programmed cell death》2003,8(2):151-160
Lewis lung carcinoma (3LL) cells were constitutively resistant to Fas-mediated apoptosis, but overexpression of Fas on 3LL cells allowed Fas-mediated apoptosis after crosslinking with agonist anti-Fas antibody (Jo2) in vitro. Surprisingly, Fas-overexpressing 3LL cells showed enhanced in vivo tumor progression, whereas no promotion of in vivo tumor growth was observed for dominant negative (DN) Fas-overexpressing 3LL transfectants in which the cytoplasmic death domain was deleted. In addition, the promotion of in vivo tumor growth by Fas-overexpression was reduced in gld (FasL-mutation) mice compared to normal mice. These data indicate that intact Fas/FasL cell signaling is required for the promotion of in vivo tumor growth by Fas overexpression in 3LL cells. In contrast to the efficient Fas-mediated killing induced in vitro by crosslinking with anti-Fas antibody, Fas-overexpressing 3LL cells were resistant in vitro to Fas-mediated apoptosis by activated T cells or transient FasL transfection. These data suggest that agonist anti-Fas antibody and natural FasL can transmit qualitatively different signals, and crosslinking of Fas with natural FasL on 3LL cells does not deliver the expected death signal. Thus, our results demonstrate that in some cases overexpression of Fas can result in a survival advantage for tumor cells in vivo. 相似文献
57.
Regulation of fas ligand expression in breast cancer cells by estrogen: functional differences between estradiol and tamoxifen 总被引:5,自引:0,他引:5
Mor G Kohen F Garcia-Velasco J Nilsen J Brown W Song J Naftolin F 《The Journal of steroid biochemistry and molecular biology》2000,73(5):185-194
During neoplastic growth and metastasis, the immune system responds to the tumor by developing both cellular and humoral immune responses. In spite of this active response, tumor cells escape immune surveillance. We previously showed that FasL expression by breast tumor plays a central role in the induction of apoptosis of infiltrating Fas-immune cells providing the mechanism for tumor immune privilege. In the present study, we showed that FasL in breast tissue is functionally active, and estrogen and tamoxifen regulate its expression. We identified an estrogen recognizing element like-motif in the promoter region of the FasL gene, suggesting direct estrogen effects on FasL expression. This was confirmed by an increase in FasL expression in both RNA and protein levels in hormone sensitive breast cancer cells treated with estradiol. This effect is receptor mediated since tamoxifen blocked the estrogenic effect. Interestingly, tamoxifen also inhibited FasL expression in estrogen-depleted conditions. Moreover, an increase in FasL in breast cancer cells induces apoptosis in Fas bearing T cells and, tamoxifen blocks the induction of apoptosis. These studies provide evidence that tamoxifen inhibits FasL expression, allowing the killing of cancer cells by activated lymphocytes. This partially explains the protective effect of tamoxifen against breast cancer. 相似文献
58.
Proteinase inhibitor 9 (PI-9, SerpinB9) is the only known human intracellular granzyme B inhibitor. Whether expression of PI-9 is sufficient to block cytolysis induced by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells remains controversial. To evaluate the roles of PI-9, we isolated and tested three lines of stably transfected HeLa cells expressing wild-type PI-9 and one line expressing an inactive mutant PI-9. Expressions of wild-type PI-9, but not the inactive mutant PI-9, inhibited cytolysis induced by human NK92 and NKL natural killer cells. Expression of high levels of PI-9 is therefore sufficient to protect human cells against NK cell-mediated cell death. Using two assays, we show that expressing wild-type PI-9, but not the inactive mutant PI-9, blocks Fas/Fas ligand (Fas/FasL)-mediated apoptosis. PI-9 expression has no effect on etoposide-induced apoptosis. HeLa cells exhibiting substantial resistance to Fas/FasL-mediated apoptosis contain 2- to 3-fold higher PI-9 levels than HCT116 human colon cancer cells and 2- to 3-fold lower PI-9 levels than MCF7/ERHA breast cancer cells, in which PI-9 is strongly induced by estrogens, and by tamoxifen. Expression of increasing levels of PI-9 in target cells may progressively inhibit immune surveillance by blocking NK and CTL-induced cytotoxicity through the perforin/granzyme pathway and then through the Fas/FasL pathway. 相似文献
59.
Accumulating evidence suggests that c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in renal ischemia/reperfusion injury. However, the downstream mechanism that accounts for the proapoptotic actions of JNK during renal ischemia/reperfusion has not been elucidated. We report that SP600125, a potent, cell-permeable, selective, and reversible inhibitor of c-Jun N-terminal kinase (JNK), potently decreased renal epithelial tubular cell apoptosis induced by renal ischemia/reperfusion via suppression of the extrinsic pathway. This corresponds to the decrease in JNK phosphorylation at 20 min and c-Jun phosphorylation (Ser63/73) at 3 h after renal ischemia. Additionally, SP600125 attenuated the increased expression of FasL induced by ischemia/reperfusion at 3 h. The administration of SP600125 prior to ischemia was also protective. Thus, our findings imply that SP600125 can inhibit the activation of the JNK-c-Jun-FasL pathway and protect renal tubular epithelial cells against ischemia/reperfusion-induced apoptosis. Taken together, these results indicate that targeting the JNK pathway provides a promising therapeutic approach for renal ischemia/reperfusion injury. 相似文献
60.
为提高对发生基因编辑细胞的筛选效率,本研究构建了具备正负筛选功能的供体质粒pN(CDS)(N2)-R,其正选择基因是无启动子NeoR,负选择基因是能自主表达的RED。利用该质粒和CRISPR-Cas9系统对小鼠B16细胞FasL进行编辑。G418筛选2周,获得混合克隆。镜下观察显示,混合克隆质量较高。junction PCR结果表明,有基因编辑发生。DNA测序结果表明,NeoR准确插入靶位点。细胞杀伤实验表明,FasL功能被有效敲除。该供体质粒的多克隆位点,充分利用同尾酶酶切位点,因而具有广泛的适用性。综上所述,在对各种位点进行编辑时,使用该供体质粒有助于混和克隆的筛选。 相似文献