Store-operated Ca2+ entry(SOCE) controls intracellular Ca2+ homeostasis and regulates a wide range of cellular events including proliferation,migration and invasion.The discovery of STIM proteins as Ca2+ sensors and O...Store-operated Ca2+ entry(SOCE) controls intracellular Ca2+ homeostasis and regulates a wide range of cellular events including proliferation,migration and invasion.The discovery of STIM proteins as Ca2+ sensors and Orai proteins as Ca2+ channel pore forming units provided molecular tools to understand the physiological function of SOCE.Many studies have revealed the pathophysiological roles of Orai and STIM in tumor cells.This review focuses on recent advances in SOCE and its contribution to tumorigenesis.Altered Orai and/or STIM functions may serve as biomarkers for cancer prognosis,and targeting the SOCE pathway may provide a novel means for cancer treatment.展开更多
The past five years have witnessed the discovery of the endoplasmic reticulum calcium(Ca2+) sensor STIM1 and the plasma membrane Ca2+channel Orai1 as the bona fide molecular components of the store-operated Ca2+ entry...The past five years have witnessed the discovery of the endoplasmic reticulum calcium(Ca2+) sensor STIM1 and the plasma membrane Ca2+channel Orai1 as the bona fide molecular components of the store-operated Ca2+ entry(SOCE) and the Ca2+ release-activated Ca2+current(I CRAC) .It has been known for two decades that SOCE and ICRAC are required for lymphocyte activation as evidenced by severe immunodeficient phenotypes in patients lacking ICRAC.In recent years however,studies have uncovered expression of STIM1 and Orai1 proteins in various tissues and described additional roles for these proteins in physiological functions and pathophysiological conditions.Here,we will summarize novel findings pertaining to the role of STIM1 and Orai1 in the vascular system and discuss their potential use as targets in the therapy of vascular disease.展开更多
OBJECTIVE:To determine the effect of Wenyang Huazhuo Fang(WHF),a Traditional Chinese Medicine decoction,on renal function in a rat model of doxorubicin-induced nephropathy,and to elucidate the underlying mechanism.MET...OBJECTIVE:To determine the effect of Wenyang Huazhuo Fang(WHF),a Traditional Chinese Medicine decoction,on renal function in a rat model of doxorubicin-induced nephropathy,and to elucidate the underlying mechanism.METHODS:Sprague-Dawley rats were randomly divided into six groups:control,doxorubicin-nephropathy,and prednisone-treated(6.45 mg·kg^-1·d^-1)doxorubicin nephropathy groups,as well as high-(7.26 g·kg^-1·d^-1),medium-(2.42 g·kg-1·d-),and low-dose(0.81 g·kg^-1·d^-1)WHF-treated doxorubicin-nephropathy groups.The nephropathy rat model was established by two tail vein injections of doxorubicin,followed by prednisone or WHF treatment for 8 weeks.Body weights were monitored and urinary protein was measured every 2 weeks.After the end of the treatment period,the rats were euthanized.Serum biochemical indicators were determined and renal morphological alterations were assessed using histological staining.The expression of transient receptor potential cation channel subfamily C member 6(TRPC6),stromal interaction molecule 1(STIM1),and calcium release-activated calcium channel protein 1(Orai1)was detected using western blotting,and their mRNA levels were examined using quantitative real-time reverse transcription-polymerase chain reaction.RESULTS:WHF treatment was found to significantly ameliorate weight loss,proteinuria,hypoalbuminemia,and dyslipidemia in doxorubicin-nephropathy rats.The protein and mRNA levels of TRPC6,STIM1,and Orai1 were partially,but significantly suppressed by prednisone or WHF treatment.CONCLUSION:Treatment with WHF significantly ameliorates renal injury in a rat model of doxorubicin-induced nephropathy,which could be at least partially related to repression of the TRPC6 pathway.展开更多
Despite the expanding knowledge on feedback regulation of Toll-like receptor （TLR） signaling, the feedforward regulation of TLR signaling for the proper innate response to invading microbes is not fully understood. ...Despite the expanding knowledge on feedback regulation of Toll-like receptor （TLR） signaling, the feedforward regulation of TLR signaling for the proper innate response to invading microbes is not fully understood. Here, we report that extracellular calcium can coordinate the activation of the small GTPases Ras and Ras-proximate-1 （Rap1） upon TLR stimulation which favors activation of macrophages through a feedforward mechanism. We show that different doses of TLR agonists can trigger different levels of cytokine production, which can be potentiated by extracellular calcium but are impaired by the chelating reagent ethylene glycol tetraacetic acid （EGTA） or by knockdown of stromal interaction molecule 1 （STIM1）. Upon TLR engagement, GTP-bound Ras levels are increased and GTP-bound Rap1 is decreased, which can be reversed by EGTA-mediated removal of extracellular calcium. Furthermore, we demonstrate that Rap1 knockdown rescues the inhibitory effects of EGTA on the TLR-triggered innate response. Examination of the TLR signaling pathway reveals that extracellular calcium may regulate the TLR response via feedforward activation of the extracellular signal-regulated kinase signaling pathway. Our data suggest that an influx of extracellular calcium, mediated by STIM 1-operated calcium channels, may transmit the information about the intensity of extracellular TLR stimuli to initiate innate responses at an appropriate level. Our study may provide mechanistic insight into the feedforward regulation of the TLR-triggered innate immune response.展开更多
文摘Store-operated Ca2+ entry(SOCE) controls intracellular Ca2+ homeostasis and regulates a wide range of cellular events including proliferation,migration and invasion.The discovery of STIM proteins as Ca2+ sensors and Orai proteins as Ca2+ channel pore forming units provided molecular tools to understand the physiological function of SOCE.Many studies have revealed the pathophysiological roles of Orai and STIM in tumor cells.This review focuses on recent advances in SOCE and its contribution to tumorigenesis.Altered Orai and/or STIM functions may serve as biomarkers for cancer prognosis,and targeting the SOCE pathway may provide a novel means for cancer treatment.
基金supported by the National Institutes of Health(Grant No. 5R01HL097111)to Mohamed Trebak
文摘The past five years have witnessed the discovery of the endoplasmic reticulum calcium(Ca2+) sensor STIM1 and the plasma membrane Ca2+channel Orai1 as the bona fide molecular components of the store-operated Ca2+ entry(SOCE) and the Ca2+ release-activated Ca2+current(I CRAC) .It has been known for two decades that SOCE and ICRAC are required for lymphocyte activation as evidenced by severe immunodeficient phenotypes in patients lacking ICRAC.In recent years however,studies have uncovered expression of STIM1 and Orai1 proteins in various tissues and described additional roles for these proteins in physiological functions and pathophysiological conditions.Here,we will summarize novel findings pertaining to the role of STIM1 and Orai1 in the vascular system and discuss their potential use as targets in the therapy of vascular disease.
基金grants from Knowlodge Innovation Projectof The Chinese Academy of Sciences(KSCX2-SW- 224, Y2004018)National Basic Research Program of China(2004CB720000)~~
基金the Key Research and Development Projects of Shaanxi Province(Study on the Effect of Wenyanghuazhuo Method on Autophagy-related Proteins in Adriamycin Nephropathy Rat Model,No.2020SF-340)a Grant from the Sci-tech Project of Shaanxi Province(Study on the Expression Regulation of STIM1/Orail and TRPC-related Channel Proteins in Renal Tissues of Adriamycin Nephropathy Rats by Aconiti Lateralis Radix and Wenyanghuazhuofang,No.2016SF-068)。
文摘OBJECTIVE:To determine the effect of Wenyang Huazhuo Fang(WHF),a Traditional Chinese Medicine decoction,on renal function in a rat model of doxorubicin-induced nephropathy,and to elucidate the underlying mechanism.METHODS:Sprague-Dawley rats were randomly divided into six groups:control,doxorubicin-nephropathy,and prednisone-treated(6.45 mg·kg^-1·d^-1)doxorubicin nephropathy groups,as well as high-(7.26 g·kg^-1·d^-1),medium-(2.42 g·kg-1·d-),and low-dose(0.81 g·kg^-1·d^-1)WHF-treated doxorubicin-nephropathy groups.The nephropathy rat model was established by two tail vein injections of doxorubicin,followed by prednisone or WHF treatment for 8 weeks.Body weights were monitored and urinary protein was measured every 2 weeks.After the end of the treatment period,the rats were euthanized.Serum biochemical indicators were determined and renal morphological alterations were assessed using histological staining.The expression of transient receptor potential cation channel subfamily C member 6(TRPC6),stromal interaction molecule 1(STIM1),and calcium release-activated calcium channel protein 1(Orai1)was detected using western blotting,and their mRNA levels were examined using quantitative real-time reverse transcription-polymerase chain reaction.RESULTS:WHF treatment was found to significantly ameliorate weight loss,proteinuria,hypoalbuminemia,and dyslipidemia in doxorubicin-nephropathy rats.The protein and mRNA levels of TRPC6,STIM1,and Orai1 were partially,but significantly suppressed by prednisone or WHF treatment.CONCLUSION:Treatment with WHF significantly ameliorates renal injury in a rat model of doxorubicin-induced nephropathy,which could be at least partially related to repression of the TRPC6 pathway.
基金This work was supported by grants from the National Key Basic Research Program of China （2010CB911903 and 2013CB530502）, the National Natural Science Foundation of China （81172851, 81222039, 31270944, and 31370902）, and the National High Technology Research and Development Program （2012AA020900）. We thank Dr. Xingguang Liu for helpful discussion and assistance with manuscript writing, and Ms. Mei Jin and Ms. Hao Shen for their excellent technical assistance.
文摘Despite the expanding knowledge on feedback regulation of Toll-like receptor （TLR） signaling, the feedforward regulation of TLR signaling for the proper innate response to invading microbes is not fully understood. Here, we report that extracellular calcium can coordinate the activation of the small GTPases Ras and Ras-proximate-1 （Rap1） upon TLR stimulation which favors activation of macrophages through a feedforward mechanism. We show that different doses of TLR agonists can trigger different levels of cytokine production, which can be potentiated by extracellular calcium but are impaired by the chelating reagent ethylene glycol tetraacetic acid （EGTA） or by knockdown of stromal interaction molecule 1 （STIM1）. Upon TLR engagement, GTP-bound Ras levels are increased and GTP-bound Rap1 is decreased, which can be reversed by EGTA-mediated removal of extracellular calcium. Furthermore, we demonstrate that Rap1 knockdown rescues the inhibitory effects of EGTA on the TLR-triggered innate response. Examination of the TLR signaling pathway reveals that extracellular calcium may regulate the TLR response via feedforward activation of the extracellular signal-regulated kinase signaling pathway. Our data suggest that an influx of extracellular calcium, mediated by STIM 1-operated calcium channels, may transmit the information about the intensity of extracellular TLR stimuli to initiate innate responses at an appropriate level. Our study may provide mechanistic insight into the feedforward regulation of the TLR-triggered innate immune response.
