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排序方式: 共有90条查询结果,搜索用时 15 毫秒
1.
Mary Steidl Matsui Isabella Illarda Nianci Wang Vincent A. DeLeo 《Experimental dermatology》1993,2(6):247-256
Abstract Several lines of evidence implicate protein kinase C (PKC) in the development of basal cell and squamous cell carcinomas, tumors which originate from epidermal keratinocytes. To examine PKC in a model relevant to human skin, we exposed normal human epidermal keratinocytes (NHEK) in serum-free media to a variety of PKC agonists and antagonists. NHEK PKC activity increased up to 10-fold within the 1st hour of exposure to tetradecanoyl phorbol acetate (TPA), and gradually returned to control values within 72 h. TPA-induced PKC activity was enhanced by pretreatment of cultures with protein and RNA synthesis inhibitors. TPA-induced growth arrest and differentiation was antagonized by staurosporine. Down-regulation by bryostatin pretreatment blocked TPA-stimulated differentiation. Our overall conclusion is that activation of PKC in cultured human keratinocytes is required for differentiation. These results are crucial to the analysis of compounds suspected of promoting or inhibiting epidermal tumors. 相似文献
2.
Recently, it has been suggested, that differentiated cells are more resistant to the apoptotic effect of DNA damaging agents
possibly due to the decreased activity of “damage detecting/apoptosis triggering” mechanism. Previously, we have shown, that
PMA pretreatment reduced etoposide-(ETO) but enhanced staurosporine- (STA) -induced apoptosis in HT58 cells. Data presented
here show that the HT58 human, “mature” B-lymphoma cells exposed to PMA secrete more IgM into the supernatant indicating commitment
of cells to perform differentiated function. The sensitivity of HT58 cells to ETO- or STA-induced apoptosis is influenced
diversely with PMA pre- or posttreatment. Interestingly, the DNA damage (gamma radiation, bleomycin, ETO) or okadaic acic
(30 nM) reduced the [PMA+STA] - induced apoptosis. 相似文献
3.
Kousi Alzoubi Jasmin Egler Marilena Briglia Antonella Fazio Caterina Faggio Florian Lang 《Toxins》2015,7(8):2822-2834
The natural phosphoprotein phosphatase inhibitor cantharidin, primarily used for topical treatment of warts, has later been shown to trigger tumor cell apoptosis and is thus considered for the treatment of malignancy. Similar to apoptosis of tumor cells, erythrocytes may undergo eryptosis, a suicidal cell death characterized by cell shrinkage and translocation of cell membrane phosphatidylserine to the erythrocyte surface. Signaling of eryptosis includes increase of cytosolic Ca2+-activity ([Ca2+]i), ceramide, oxidative stress and dysregulation of several kinases. Phosphatidylserine abundance at the erythrocyte surface was quantified utilizing annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ceramide from antibody binding, and reactive oxidant species (ROS) from 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence. A 48 h treatment of human erythrocytes with cantharidin significantly increased the percentage of annexin-V-binding cells (≥10 μg/mL), significantly decreased forward scatter (≥25 μg/mL), significantly increased [Ca2+]i (≥25 μg/mL), but did not significantly modify ceramide abundance or ROS. The up-regulation of annexin-V-binding following cantharidin treatment was not significantly blunted by removal of extracellular Ca2+ but was abolished by kinase inhibitor staurosporine (1 μM) and slightly decreased by p38 inhibitor skepinone (2 μM). Exposure of erythrocytes to cantharidin triggers suicidal erythrocyte death with erythrocyte shrinkage and erythrocyte membrane scrambling, an effect sensitive to kinase inhibitors staurosporine and skepinone. 相似文献
4.
The identification of FLT3 mutations across a range of the cytogenetic subgroups of AML has opened up the possibility of a targeted therapeutic approach with broad applicability. Four agents are currently in clinical trials, at least 3 of which have both sufficient activity against AML and sufficiently acceptable toxicity profiles to support continued efforts to refine their inclusion into therapeutic regimens for AML. Better understanding of the genetics of inherent and acquired resistance is needed to guide development of second-generation agents. Optimizing the integration of FLT3 inhibitor therapy with chemotherapy has the potential both to decrease toxicity and improve response. 相似文献
5.
We are interested in studying the possibility of modulating prostatic cell growth by manipulating apoptosis. Here we show that 1 μM staurosporine (STS) induces a human androgen-independent prostatic tumor cell line, DU145, to undergo dramatic changes in morphology and results in programmed cell death. Several genes involved in apoptosis were analyzed for expression in STS-treated and untreated DU145 cells. It was observed that these genes were differentially regulated. The expression level of bcl-2, bcl-xL, Ich-1L remains unchanged in treated and untreated cells. On the other hand, DAD1 and interleukin-1β-converting enzyme (ICE) were downregulated while bcl-xs and Ich-1s were upregulated. By blocking bcl-2 gene expression using antisense oligonucleotides, it was determined that the anti-bcl-2 oligonucleotides have no effect on the proliferation of DU145 or STS-treated DU145 cells. These results demonstrate that programmed cell death can be induced in an androgen-independent prostatic cancer cell line and BCL-2 was found not to play an important role in preventing STS-induced apoptosis in the DU145 cell line. © 1996 Wiley-Liss, Inc. 相似文献
6.
We have examined whether p21Ras proteins can rescue nerve growth factor-deprived rat sympathetic neurons from death, to test further our hypothesis that p21Ras is a central mediator in the nerve growth factor-to-survival signalling pathway. After crosslinking ]125I]nerve growth factor to live neurons, two forms of Trk (molecular weight 140,000 and 115,000) were immunoprecipitated with anti-Trk antibodies. Nerve growth factor induced tyrosine phosphorylation of both Trk forms and at least two additional proteins. When these phosphorylations were prevented by staurosporine (in a protein kinase C-independent manner) the neurons died. However, neurons were rescued from death due to staurosporine treatment by intracellular loading of oncogenic Ha-Ras(val12) protein. Both Ha-Ras(val12) and cellular Ha-Ras proteins maintained survival for several days in the absence of nerve growth factor and mimicked other actions of nerve growth factor, inducing rapid c-Fos protein expression and robust neurite outgrowth. Conversely, Fab fragments of neutralizing antibodies to p21Ras which blocked the capacity of nerve growth factor to promote neuron survival were also found to inhibit the early expression of c-Fos protein in these neurons. The close correspondence observed between the timing of onset of c-Fos responsiveness and acquisition of nerve growth factor-dependence in embryonic day 17 sympathetic neurons, and the coordinate increase found in both parameters until embryonic day 19 indicates that c-Fos protein expression is a good biochemical indicator of the presence of a functional nerve growth factor-to-survival signal transduction pathway. Nevertheless, expression of c-Fos is not sufficient for survival since phorbol esters induce c-Fos with no effect on survival.
These data strengthen our proposal that p21Ras proteins are crucial anti-apoptotic mediators of survival in rat sympathetic neurons by demonstrating that p21Ras is both necessary and sufficient to rescue neurons which are disabled from signalling through Trk receptors. 相似文献
7.
星形孢菌素诱导NG108—15细胞凋亡 总被引:5,自引:2,他引:3
目的:研究星形孢菌素是否能引起NG108—15细胞的凋亡及它对数种与凋亡相关基因蛋白表达水平的影响.方法:用相差显微镜、荧光显微镜和透射电镜观察形态学变化;琼脂糖凝胶电泳检测DNA梯带;免疫印迹法检测凋亡相关基因蛋白的表达水平.结果:经星形孢菌素0.1μmol/L处理后NG108—15细胞呈典型的凋亡形态学变化.星形孢菌素处理后6h即出现DNA凋亡梯带,可持续至24h.Bax蛋白表达在星形孢菌素处理后6h开始上升,12h至最高峰,24h后下降.Bcl-2蛋白表达在星形孢菌素处理后3h明显上升,随后逐渐下降.星形孢菌素处理后6h可见caspase-3切割产物出现,但Cdk5蛋白的表达水平未见明显变化.p53蛋白表达在星形孢菌素处理12h后下降.结论:星形孢菌素诱导了NG108—15细胞的凋亡,可能与Bax蛋白表达的增加及caspase-3切割有关,而与p53和Cdk5无明显相关性. 相似文献
8.
Understanding the regulation of cell death pathways is critical for protecting myelin-producing cells and their associated axons during injury resulting from multiple sclerosis and other degenerative diseases. The immortalized N20.1 oligodendroglial cell line provides a useful model for identifying mechanisms that can be exploited to attenuate cell death in myelin-producing cells and their precursors. In our hands, the N20.1 cell line exhibits different characteristics and morphology depending on temperature (permissive or non-permissive) and the presence of cAMP-elevating agents (Studzinski et al. [1998] Neurochem. Res. 23:435-441; Boullerne et al. [1999] J. Neurochem. 72:1050-1060; Studzinski et al. [1999] J. Neurosci. Res. 57:633-642). Our laboratory previously observed that NO donors cause primarily necrotic death in N20.1 cells grown at permissive temperature, but the NO donor SNP switched a portion of cell death to the apoptic pathway. We have continued our study of apoptotic death in these cells by comparing the effects of staurosporine, a known apoptotic agent, on cells grown at the permissive temperature ("undifferentiated") vs. the non-permissive temperature in the presence of forskolin ("differentiated"). Undifferentiated N20.1 cells exhibit maximal cell death after 24 hr of exposure to 50 nM staurosporine, whereas differentiated cells show delayed cell death, with maximal death seen after 48 hr. Pyknotic nuclei were observed in both growth conditions; however, differentiated cells were protected by caspase inhibitors, whereas undifferentiated cells were not. Increased ssDNA staining and DNA laddering were found following 24-hr staurosporine treatment in the differentiated cells only. These results support the conclusion that N20.1 cells can switch from necrotic to apoptotic cell death when cell division is slowed and cyclic AMP is elevated. 相似文献
9.
Lash LH Putt DA Hueni SE Cao W Xu F Kulidjian SJ Horwitz JP 《Biochemical pharmacology》2002,64(10):1533-1546
Cellular energetics and redox status were evaluated in NRK-52E cells, a stable cell line derived from rat proximal tubules. To assess toxicological implications of these properties, susceptibility to apoptosis induced by S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a well-known mitochondrial and renal cytotoxicant, was studied. Cells exhibited high activities of several glutathione (GSH)-dependent enzymes, including gamma-glutamylcysteine synthetase, GSH peroxidase, glutathione disulfide reductase, and GSH S-transferase, but very low activities of gamma-glutamyltransferase and alkaline phosphatase, consistent with a low content of brush-border microvilli. Uptake and total cellular accumulation of [14C]alpha-methylglucose was significantly higher when cells were exposed at the basolateral as compared to the brush-border membrane. Similarly, uptake of GSH was nearly 2-fold higher across the basolateral than the brush-border membrane. High activities of (Na(+)+K(+))-ATPase and malic dehydrogenase, but low activities of other mitochondrial enzymes, respiration, and transport of GSH and dicarboxylates into mitochondria were observed. Examination of mitochondrial density by confocal microscopy, using a fluorescent marker (MitoTracker Orange), indicated that NRK-52E cells contain a much lower content of mitochondria than rat renal proximal tubules in vivo. Incubation of cells with DCVC caused time- and concentration-dependent ATP depletion that was largely dependent on transport and bioactivation, as observed in the rat, on induction of apoptosis, and on morphological damage. Comparison with primary cultures of rat and human proximal tubular cells suggests that the NRK-52E cells are modestly less sensitive to DCVC. In most respects, however, NRK-52E cells exhibited functions similar to those of the rat renal proximal tubule in vivo. 相似文献
10.