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991.
Qu J Cammarano MS Shi Q Ha KC de Lanerolle P Minden A 《Molecular and cellular biology》2001,21(10):3523-3533
The serine/threonine kinase PAK4 is an effector molecule for the Rho GTPase Cdc42. PAK4 differs from other members of the PAK family in both sequence and function. Previously we have shown that an important function of this kinase is to mediate the induction of filopodia in response to activated Cdc42. Since previous characterization of PAK4 was carried out only with the wild-type kinase, we have generated a constitutively active mutant of the kinase to determine whether it has other functions. Expression of activated PAK4 in fibroblasts led to a transient induction of filopodia, which is consistent with its role as an effector for Cdc42. In addition, use of the activated mutant revealed a number of other important functions of this kinase that were not revealed by studying the wild-type kinase. For example, activated PAK4 led to the dissolution of stress fibers and loss of focal adhesions. Consequently, cells expressing activated PAK4 had a defect in cell spreading onto fibronectin-coated surfaces. Most importantly, fibroblasts expressing activated PAK4 had a morphology that was characteristic of oncogenic transformation. These cells were anchorage independent and formed colonies in soft agar, similar to what has been observed previously in cells expressing activated Cdc42. Consistent with this, dominant-negative PAK4 mutants inhibited focus formation by oncogenic Dbl, an exchange factor for Rho family GTPases. These results provide the first demonstration that a PAK family member can transform cells and indicate that PAK4 may play an essential role in oncogenic transformation by the GTPases. We propose that the morphological changes and changes in cell adhesion induced by PAK4 may play a direct role in oncogenic transformation by Rho family GTPases and their exchange factors. 相似文献
992.
Zhang Zhuo Leonard Stephen S. Wang Suwei Vallyathan Val Castranova Vince Shi Xianglin 《Molecular and cellular biochemistry》2001,222(1-2):77-83
Cr (VI) compounds are widely used in industries and are recognized human carcinogens. The mechanism of carcinogenesis associated with these compounds is not well understood. The present study focused on Cr (VI)induced cell growth arrest in human lung epithelial A549 cells, using flow cytometric analysis of DNA content. Treatment of the cells with Cr (VI) at 1 M caused a growth arrest at G2/M phase. An increase in Cr (VI) concentration enhanced the growth arrest. At a concentration of 25 M, Cr (VI)induced apoptosis became apparent. Superoxide dismutase (SOD) or sodium formate did not alter the Cr (VI)induced cell growth arrest. While catalase inhibited growth, indicating H2O2 is an important mediator in Cr (VI)induced G2/M phase arrest. Electron spin resonance (ESR) spin trapping measurements showed that incubation of cells with Cr (VI) generated hydroxyl radical (OH). Catalase inhibited the OH radical generation, indicating that H2O2 was generated from cells stimulated by Cr (VI), and that H2O2 functioned as a precursor for OH radical generation. The formation of H2O2 from Cr (VI)stimulated cells was also measured by the change in fluorescence of scopoletin in the presence of horseradish peroxidase. The mechanism of reactive oxygen species generation involved the reduction of molecular oxygen as shown by oxygen consumption assay. These results support the following conclusions: (a) Reactive oxygen species are generated in Cr (VI)stimulated A549 cells through reduction of molecular oxygen, (b) Among the reactive oxygen species generated, H2O2 played a major role in causing G2/M phase arrest in human lung epithelial cells. 相似文献
993.
Distinct apoptotic phenotypes induced by radiation and ceramide in both p53-wild-type and p53-mutated lymphoblastoid cells 总被引:1,自引:0,他引:1
Shi YQ Wuergler FE Blattmann H Crompton NE 《Radiation and environmental biophysics》2001,40(4):301-308
The tumour suppressor gene p53 and the intracellular signalling molecule ceramide have both been shown to play crucial roles
in the induction of apoptosis by ionising radiation. In this study we examined whether p53 and ceramide are involved in independent
signal pathways, inducing different types of apoptosis. TK6 (p53wt/wt) and WTK1 (p53mut/mut) lymphoblastoid cells were treated with ionising radiation or N-acetyl-d-sphingosine (C2-ceramide). Flow cytometry and fluorescence microscopy studies were performed to characterise the time kinetics and morphological
features of induced apoptosis. Ceramide- and radiation-induced apoptotic cells display characteristic differences in morphology
and DNA staining and ceramide-induced apoptosis is expressed much faster than radiation-induced apoptosis. Radiation-induced
apoptosis is p53-dependent and ceramide-induced apoptosis is p53-independent. The p53 pathway and the ceramide pathway are
two independent signal pathways leading to distinct types of apoptosis. Since p53 is very often dysfunctional in tumour cells,
modifying the ceramide pathway is a promising strategy to increase tumour sensitivity to radiation and other anticancer agents.
Received: 19 April 2001 / Accepted: 15 October 2001 相似文献
994.
失血性休克引起大鼠肠系膜动脉平滑肌依钙K^+通道活动改变 总被引:10,自引:0,他引:10
在由股动脉放血制备的失血性休克大鼠模型急性分离的肠系膜动脉平滑肌细胞上,利用膜片箝单通道记录技术观察了血管平滑肌依钙K^ 通道(BKca)的活动,发现在对去甲肾上腺素(NE)反应性增高的休克代偿期,BKca的开放概率(P0)和单位电导都显著较正常动物的低,P0的改变主要是由通道的慢关闭时间常数(τcs)增大引起关闭时间延长所致;而处于对NE反应性降低的休克失代偿期,BKca的P0和单位电导都高于正常动物,P0的变化也主要是τcs减小所致。 相似文献
995.
肾缺血增强大鼠延髓腹外侧头端区神经元电话动和Fos蛋白表达 总被引:2,自引:0,他引:2
在67只切断两侧缓冲神经的麻醉Sprague-Dawley大鼠,应用细胞外记录的电生理方法和免疫组织化学技术,分别观察肾缺血对延髓腹外侧头端区巨细胞旁外侧核神经元自发放电活动和Fos蛋白表达的影响.所得结果如下(1)左肾动脉阻断后,28个单位的放电频率由11.40±1.08增至21.1±1.74spikes/s(P<0.001),血压和心率无明显变化(P>0.05);(2)在17个放电单位中,应用腺苷受体拮抗剂8-苯茶碱(8-phenyltheophylline,10mg/kg)可明显抑制肾缺血的兴奋效应(P<0.05);(3)肾缺血后,延髓腹外侧头端区的Fos蛋白样免疫反应神经元显著增加(P<0.01);(4)预先应用8-苯茶碱可明显减弱肾缺血所激活的Fos蛋白表达反应(P<0.05).以上结果提示肾缺血增强延髓腹外侧头端区神经元的放电活动和Fos蛋白表达,而此作用可能与肾脏缺血所产生的腺苷激活肾内感受器有关. 相似文献
996.
实验采用NADPH-d组化技术和Fos蛋白免疫组化技术相结合的方法,观察了颈动脉注射辣椒不时,大鼠脑干心血管相关核团内NOS和Fos蛋白的分布以及两者的共存关系。结果显示:(1)颈动脉注射辣椒不可诱发脑干中最后区(AP)、孤束核(NTS)、巨细胞旁外侧核(PGL)和蓝斑(LC)等多个部位Fos样免疫反应(FLI)神经元显著增加 中脑中央灰质(PAG)和中缝核群(RN)的FLI神经元无明显改变。(2)PGL和NTS内NO合成神经元以及PGL内双标神经元数量也明显增加,而AG和RN中NO合成神经元无明显变化,在LC和AP仅偶见或未见NO合成神经元。(3)预先应用辣椒素受体阻断剂钌红或NMDA受体阻断剂MK-801,则明显减弱辣椒素的上述效应,以上结果表明,颈动脉注射辣椒素可兴奋脑干心血管活动相关核团神经元,NO在脑干核团对辣椒素的反应中发挥间接的调制作用,辣椒素的效应由香草酸受体(辣椒素受体)介导并有谷氨酸参与。 相似文献
997.
998.
The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/beta-catenin signalling 下载免费PDF全文
Umbhauer M Djiane A Goisset C Penzo-Méndez A Riou JF Boucaut JC Shi DL 《The EMBO journal》2000,19(18):4944-4954
Frizzled receptors are components of the Wnt signalling pathway, but how they activate the canonical Wnt/beta-catenin pathway is not clear. Here we use three distinct vertebrate frizzled receptors (Xfz3, Xfz4 and Xfz7) and describe whether and how their C-terminal cytoplasmic regions transduce the Wnt/beta-catenin signal. We show that Xfz3 activates this pathway in the absence of exogenous ligands, while Xfz4 and Xfz7 interact with Xwnt5A to activate this pathway. Analysis using chimeric receptors reveals that their C-terminal cytoplasmic regions are functionally equivalent in Wnt/beta-catenin signalling. Furthermore, a conserved motif (Lys-Thr-X-X-X-Trp) located two amino acids after the seventh transmembrane domain is required for activation of the Wnt/beta-catenin pathway and for membrane relocalization and phosphorylation of Dishevelled. Frizzled receptors with point mutations affecting either of the three conserved residues are defective in Wnt/beta-catenin signalling. These findings provide functional evidence supporting a role of this conserved motif in the modulation of Wnt signalling. They are consistent with the genetic features exhibited by Drosophila Dfz3 and Caenorhabditis elegans mom-5 in which the tryptophan is substituted by a tyrosine. 相似文献
999.
1000.
Major histocompatibility complex (MHC) class II molecules bind and present to CD4(+) T cells peptides derived from endocytosed antigens. Class II molecules associate in the endoplasmic reticulum with invariant chain (Ii), which (i) mediates the delivery of the class II-Ii complexes into the endocytic compartments where the antigenic peptides are generated; and (ii) blocks the peptide-binding site of the class II molecules until they reach their destination. Once there, Ii must be removed to allow peptide binding. The bulk of Ii-class II complexes reach late endocytic compartments where Ii is eliminated in a reaction in which the cysteine protease cathepsin S and the accessory molecule H-2DM play an essential role. Here, we here show that Ii is also eliminated in early endosomal compartments without the intervention of cysteine proteases or H-2DM. The Ii-free class II molecules generated by this alternative mechanism first bind high molecular weight polypeptides and then mature into peptide-loaded complexes. 相似文献