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多囊蛋白2 (polycystin-2,PC2,或称TRPP2,PKD2)是一种瞬时受体电位通道(transient receptor potential channel,TRP),在维持细胞正常的Ca2+信号传导中起着关键作用,也是最常见的单基因常染色体显性遗传多囊肾病(transient receptor potential channel,ADPKD)的潜在病因之一。PC2可自身组装为同源四聚体离子通道或与其他蛋白质形成异源受体-离子通道复合物,参与调节机械感觉、细胞极性、细胞增殖和凋亡等多种生理功能,导致囊性细胞从正常的吸收、静止状态转变为病理性分泌、增殖状态。本文阐述了PC2蛋白相关结构域以及通道特性在维持细胞内Ca2+信号传导中的关键作用,并总结了PC2在细胞膜、纤毛、内质网以及线粒体等特定亚细胞定位形成多囊蛋白复合物,参与多种细胞分化、增殖、存活和凋亡相关信号通路,为确定特异性的有效的ADPKD干预治疗途径和靶点药物提供新的思考方向。 相似文献
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目的:PKD2(polycystin2,多囊肾病蛋白2)能够在细胞膜上形成无选择性的阳离子通道,在肾上皮细胞中PKD2与初级纤毛共定位,通过改变胞内的钙信号过程参与细胞对力学刺激的响应。本实验通过二维回转培养来模拟失重效应,旨在探讨二维回转培养对MLO-Y4骨样细胞PKD2表达定位,及胞内钙信号的影响。初步了解PKD2在小鼠骨样细胞MLO-Y4响应力学刺激过程中起的作用。方法:采用二维回转培养骨样细胞MLO-Y4,用RT-PCR和western blotting检测PKD2的表达,用荧光共聚焦显微镜检测细胞中PKD2与初级纤毛的定位及细胞内钙离子含量。结果:与对照组相比,在二维回转培养后,骨样细胞MLO-Y4的PKD2表达在mRNA和蛋白水平都有明显的下降,PKD2、PKD1(polycystin1,多囊肾病蛋白1)和乙酰化的α-tubulin共定位,同时二维回转培养降低了细胞内钙离子含量。结论:在二维回转培养下,PKD2可能通过调节自身表达来改变细胞膜上PKD通道的数目和开放情况来影响细胞内钙离子含量,参与骨细胞对细胞外应力的感受过程,其详细机制还有待进一步实验研究。这将对探讨骨细胞响应力学刺激的具体机制提供重要的理论依据。 相似文献
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目的:PKD2(polycystin2,多囊肾病蛋白2)能够在细胞膜上形成无选择性的阳离子通道,在肾上皮细胞中PKD2 与初级纤毛
共定位,通过改变胞内的钙信号过程参与细胞对力学刺激的响应。本实验通过二维回转培养来模拟失重效应,旨在探讨二维回转
培养对MLO-Y4 骨样细胞PKD2 表达定位,及胞内钙信号的影响。初步了解PKD2 在小鼠骨样细胞MLO-Y4 响应力学刺激过程
中起的作用。方法:采用二维回转培养骨样细胞MLO-Y4,用RT-PCR和western blotting检测PKD2的表达,用荧光共聚焦显微镜
检测细胞中PKD2 与初级纤毛的定位及细胞内钙离子含量。结果:与对照组相比,在二维回转培养后,骨样细胞MLO-Y4 的PKD2
表达在mRNA和蛋白水平都有明显的下降,PKD2、PKD1(polycystin1,多囊肾病蛋白1)和乙酰化的α-tubulin 共定位,同时二维回
转培养降低了细胞内钙离子含量。结论:在二维回转培养下,PKD2可能通过调节自身表达来改变细胞膜上PKD 通道的数目和开
放情况来影响细胞内钙离子含量,参与骨细胞对细胞外应力的感受过程,其详细机制还有待进一步实验研究。这将对探讨骨细胞
响应力学刺激的具体机制提供重要的理论依据。 相似文献
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李新华 《中国细胞生物学学报》2022,(11):2171-2182
纤毛是由微管组成,存在于大部分细胞表面呈头发状结构的细胞器。根据纤毛是否运动,可以将其分为初级纤毛和动纤毛(多纤毛)。动纤毛常分布于大脑中央水管上皮、气道上皮、生殖系统的输卵管上皮组织等处。初级纤毛则分布于其余的大部分组织器官的细胞内,例如肾小管上皮细胞、各骨细胞或者软骨细胞、椎间盘细胞等。初级纤毛被认为是细胞把外界信号转导到细胞内的机械信号或者化学感受器和多种信号通路转导的中心。运动系统是由骨、软骨、关节、肌腱等组织组成,具有运动、支持、保护功能的人体主要承受力学的系统。因此,作为人体机械信号感受器的初级纤毛被认为与人体运动系统正常生理功能的维持密切相关。参与纤毛形成的基因突变可导致纤毛缺失,从而引起运动系统的多组织器官异常。同时,人们也发现在骨性关节炎、椎间盘退变、脊柱侧弯等许多常见的运动系统疾病中存在初级纤毛异常。因此,深入研究初级纤毛在运动系统组织器官生理功能维持及与疾病的关系有助于运动系统疾病的治疗。该文对初级纤毛与运动系统疾病的研究进展进行综述,指出了纤毛与运动系统疾病的最新进展及重点与难点,为运动系统疾病的发病机制研究提供理论参考。 相似文献
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《中国科学:生命科学》2016,(4)
纤毛(cilia)是细胞表面的突起状细胞器,几乎存在于所有细胞表面,且广泛分布于组织和器官的上皮.纤毛由外部的纤毛膜和内部的轴丝组成,结构在进化上十分保守.根据微管组成和排列方式的不同,纤毛可分为9+2型运动纤毛与9+0型基本纤毛或非运动纤毛.作为一种特殊的感受器,纤毛通过影响细胞信号通路参与胚胎形成、心脏等内脏器官发育及人体重要生理活动.本课题组在国际上首次把前列腺素信号通路与纤毛生长及心脏发育相联系.研究发现,ABCC4/LKT前列腺素转运蛋白从细胞内运输前列腺素E2(PGE2)至细胞外,并通过结合位于纤毛膜上的G蛋白偶联受体EP4影响细胞内c AMP浓度,调节纤毛内运输蛋白的正向速率,进而调控纤毛生长与心脏等器官的左右不对称性发育.纤毛生长或功能缺陷会引发先天性心脏病、多囊肾、视网膜变性等多种疾病.本文主要介绍纤毛参与调控细胞内信号转导与器官发育及相关纤毛疾病. 相似文献
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初级纤毛是一类以微管为基础结构的细胞器,其来源于细胞的母中心粒,锚定在细胞膜并如“天线”般突出细胞表面。作为细胞感受器,初级纤毛从环境中接受各种信号,传导至细胞内引起细胞反应。近期的研究表明,初级纤毛对与胚胎发育密切相关的Wnt信号通路的传导起重要作用。纤毛的损害可造成Wnt信号通路的异常,并引起胚胎中多类脏器一系列的病理改变,导致初级纤毛相关疾病的发生。文章主要阐述了初级纤毛与Wnt/β-catenin、Wnt/PCP通路及初级纤毛相关疾病之间的关系,并对初级纤毛相关疾病的治疗进行了初步探讨。对初级纤毛与Wnt信号通路关系的深入研究将有助于人们对该类疾病的进一步诊断和治疗。 相似文献
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细胞内信号传递与转录调控的研究进展 总被引:3,自引:0,他引:3
石缨 《国外医学:分子生物学分册》1997,19(5):201-204
综合近年来有关细胞内信号传递与转录调控的研究进展,总结出3个细胞内信号传递系统-MAP激酶途径、JAK/STAT途径和NK-kB途径,细胞外信号分别通过以上3种途径,在细胞核、细胞膜、细胞浆中激活转录因子,调控基因表达,其中可逆性磷酸化对转录因子活性的调节起着重要的作用。 相似文献
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Wnt信号传导途径的调控失常是导致多种类型的细胞发生癌变的主要原因之一,该途径成员之一beta-连环蛋白/T细胞因子4的激活可促进癌变,而另一成员ICAT通过阻止beta-连环蛋白/T细胞因子4复合物的形成而对Wnt信号传导途径进行负调控来发挥抑癌作用。现综述ICAT蛋白抑瘤机制新进展。 相似文献
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Polycystic kidney disease: new understanding in the pathogenesis 总被引:8,自引:0,他引:8
Wilson PD 《The international journal of biochemistry & cell biology》2004,36(10):1868-1873
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A tale of two tails: ciliary mechanotransduction in ADPKD 总被引:3,自引:0,他引:3
Cantiello HF 《Trends in molecular medicine》2003,9(6):234-236
Autosomal dominant polycystic kidney disease (ADPKD) is a common lethal genetic disorder, characterized by the progressive development of fluid-filled cysts in the kidney, pancreas and liver, and anomalies of the cardiovascular system. Mutations in PKD1 and PKD2, which encode the transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2) respectively, account for almost all cases of ADPKD. However, the mechanisms by which abnormalities in PKD1 and PKD2 lead to aberrant kidney development remain unknown. Recent progress in the understanding of ADPKD has focused on primary cilia, which act as sensory transducers in renal epithelial cells. New evidence shows that a mechanosensitive signal, cilia bending, activates the PC1-PC2 channel complex. When working properly, this functional complex elicits a transient Ca(2+) influx, which is coupled to the release of Ca(2+) from intracellular stores. 相似文献
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Nguyen AN Jansson K Sánchez G Sharma M Reif GA Wallace DP Blanco G 《American journal of physiology. Renal physiology》2011,301(4):F897-F906
The Na-K-ATPase is part of a cell signaling complex, the Na-K-ATPase signalosome, which upon activation by the hormone ouabain regulates the function of different cell types. We previously showed that ouabain induces proliferation of epithelial cells derived from renal cysts of patients with autosomal dominant polycystic kidney disease (ADPKD cells). Here, we investigated the signaling pathways responsible for mediating the effects of ouabain in these cells. Incubation of ADPKD cells with ouabain, in concentrations similar to those found in blood, stimulated phosphorylation of the epidermal growth factor receptor (EGFR) and promoted its association to the Na-K-ATPase. In addition, ouabain activated the kinase Src, but not the related kinase Fyn. Tyrphostin AG1478 and PP2, inhibitors of EGFR and Src, respectively, blocked ouabain-dependent ADPKD cell proliferation. Treatment of ADPKD cells with ouabain also caused phosphorylation of the caveolar protein caveolin-1, and disruption of cell caveolae with methyl-β-cyclodextrin prevented Na-K-ATPase-EGFR interaction and ouabain-induced proliferation of the cells. Downstream effects of ouabain in ADPKD cells included activation of B-Raf and MEK and phosphorylation of the extracellular regulated kinase ERK, which translocated into the ADPKD cell nuclei. Finally, ouabain reduced expression of the cyclin-dependent kinase inhibitors p21 and p27, which are suppressors of cell proliferation. Different from ADPKD cells, ouabain showed no significant effect on B-Raf, p21, and p27 in normal human kidney epithelial cells. Altogether, these results identify intracellular pathways of ouabain-dependent Na-K-ATPase-mediated signaling in ADPKD cells, including EGFR-Src-B-Raf-MEK/ERK, and establish novel mechanisms involved in ADPKD cell proliferation. 相似文献
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Autosomal dominant polycystic kidney disease (ADPKD) is a progressive chronic kidney disease. To date there are no effective medicines to halt development and growth of cysts. In the present study, we explored novel effects of celecoxib (CXB), a COX-2 specific inhibitor, on primary cultures of human ADPKD cyst-lining epithelial cells. Primary cultures of ADPKD cyst-lining epithelial cells were obtained from five patients. Effects of CXB were measured by various assays to detect BrdU incorporation, apoptosis and proliferation in vitro. Additionally, effects of CXB on kidney weight, the cyst index, the fibrosis index, blood urea nitrogen (BUN), serum creatinine (SCr), serum 6-keto-PGF-1α, serum thromboxane-2 (TXB2) and renal PCNA expression were assessed in Han:SPRD rat, a well-characterized rodent model of PKD. CXB inhibited proliferation of ADPKD cyst-lining epithelial cells, blocked the release of VEGF from the cells and induced extensive apoptosis in a time- and dose-dependent manner. Moreover, CXB up-regulated the cell cycle negative regulator p21(CIP/WAF1) and the cell cycle positive regulator Cyclin A, blocked ERK1/2 phosphorylation, induced apoptotic factors (Bax and caspase-3) and reduced Bcl-2. Furthermore, CXB inhibited the expression of VEGFR-2 and Raf-1 in ADPKD cyst-lining epithelial cells. CXB markedly reduced the cyst index, the fibrosis index, leukocyte infiltration, BUN, SCr, serum 6-keto-PGF-1α, TXB2 and renal PCNA expression in Han:SPRD rat. We demonstrated for the first time that CXB could suppress renal cyst-lining growth both in vitro and in vivo in Han:SPRD rat. CXB can inhibit proliferation, suppress cell cycle progression, and induce apoptosis in ADPKD cyst-lining epithelial cells through the inhibition of the VEGF/VEGFR-2/Raf-1/MAPK/ERK signaling pathway. 相似文献
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Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation initiated by dedifferentiation and
proliferation of renal tubular epithelial cells. Renal tubular epithelial cells (RTC, derived from normal kidney tissue) in
primary cultures exhibit both homogeneous expression of γ-glutamyl transferase and low molecular weight cytokeratin, two different
markers for proximal and distal renal epithelial cells, respectively. RTC in cultures also abnormally express the dedifferentiation
markers vimentin and PAX-2, which are proteins normally expressed in epithelial cells lining cysts in ADPKD kidneys but not
tubular cells in normal kidneys. In contrast, different cultures of cystic epithelial cells (CEC, derived from the cysts walls
of polycystic kidneys) display variable expression of cytokeratin, γ-glutamyl transferase, and PAX-2, but a constant level
of vimentin. Importantly, RTC and CEC exhibit the capacity to convert to their respective original structures by forming tubules
and cysts, respectively, when cultured in a three-dimensional gel matrix, whereas HK-2, LLC-PK1, and MDCK renal epithelial
cell lines form cell aggregates or cysts. Our study demonstrates that the marker expression of the various epithelial cell
types is not highly stable in primary cultures. Their modulation is different in cells originating from normal and ADPKD kidneys
and in cells cultured in monolayer and three-dimensions. These results indicate the plasticity of epithelial cells that display
a mixed epithelial/dedifferentiated/mesenchymal phenotype during their expansion in culture. However, RTC and CEC morphogenic
epithelial properties in three-dimensional cultures are similar to those in vivo. Thus, this model is useful for studying
the mechanisms leading to tubulogenesis and cystogenesis.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
This work was supported by a grant from The Polycystic Kidney Foundation. We gratefully acknowledge the support of the Children’s
Medical Research Institute and Children’s Miracle Network Foundation. 相似文献
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Polycystins, calcium signaling, and human diseases 总被引:9,自引:0,他引:9
Delmas P Padilla F Osorio N Coste B Raoux M Crest M 《Biochemical and biophysical research communications》2004,322(4):1374-1383
Autosomal dominant polycystic kidney disease (ADPKD) is a major, inherited nephropathy affecting over 1:1000 of the worldwide population. It is a systemic condition with frequent hepatic and cardiovascular manifestations in addition to the progressive development of fluid-filled cysts from the tubules and collecting ducts of affected kidneys. The pathogenesis of cyst formation is currently thought to involve increased proliferation of epithelial cells, mild dedifferentiation, and fluid accumulation. In the past decade, study of ADPKD led to the discovery of a unique family of highly complex proteins, the polycystins. Loss-of-function mutations in either of two polycystin proteins, polycystin-1 or polycystin-2, give rise to ADPKD. These proteins are thought to function together as part of a multiprotein complex that may initiate Ca2+ signals, directing attention to the regulation of intracellular Ca2+ as a possible misstep that participates in cyst formation. Here we review what is known about the Ca2+ signaling functions of polycystin proteins and focus on findings that have significantly advanced our physiological insight. Special attention is paid to the recently discovered role of these proteins in the mechanotransduction of the renal primary cilium and the model it suggests. 相似文献
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The exocyst localizes to the primary cilium in MDCK cells 总被引:4,自引:0,他引:4
Rogers KK Wilson PD Snyder RW Zhang X Guo W Burrow CR Lipschutz JH 《Biochemical and biophysical research communications》2004,319(1):138-143
Primary cilia play a role in the maintenance of tubular epithelial differentiation and ciliary dysfunction can result in abnormal cyst formation, such as occurs in autosomal dominant polycystic kidney disease (ADPKD). We previously showed that the exocyst, an eight-protein complex involved in the biogenesis of polarity from yeast to mammals, is centrally involved in cyst formation [Mol. Biol. Cell. 11 (2000) 4259]. Here we show that the exocyst complex localizes to the primary cilium in Madin-Darby canine kidney (MDCK) tubular epithelial cells. We further show that the exocyst is overexpressed in both cell lines and primary cell cultures of ADPKD origin, suggesting that the exocyst may be involved in the pathogenesis of ADPKD. 相似文献
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