GHS-R在垂体生长激素腺瘤生长激素分泌和细胞增殖中的作用及机制研究
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摘要
目的研究生长激素释放肽-6(GHRP-6)与其受体(GHS-R)结合后细胞内的信号传导机制,检测信号传导通路中发挥主要作用的蛋白激酶C(PKC)亚型。
方法首先检测GHRP-6对大鼠垂体GH腺瘤细胞系GH3细胞生长激素(GH)分泌和cAMP反应元件结合蛋白(CREB)磷酸化的调节作用。然后对GHRP-6诱导激活的PKC亚型进行初步筛选：应用PKC广谱激动剂佛波醇酯(PMA)和两种PKC抑制剂(Go6983和rottlerin)干预GH3细胞。对初步筛选出的PKC亚型进行RNA干扰,沉默其表达,以确定该亚型的作用：根据Genebank数据库提供的基因核苷酸序列设计干扰序列,由生物公司帮助合成；利用lipo2000作为载体转染GH3细胞。转染后,应用Western blot检测该亚型的蛋白表达,以确定转染效率。同时检测基因沉默该亚型后,GHRP-6对GH分泌和CREB磷酸化的调节作用的变化。并检测GHRP-6作用后该亚型的活性。
结果GHRP-6诱导GH分泌呈时间和浓度依赖性(P<0.05),并且可以增强生长激素释放激素(GHRH)的作用(P<0.05)。GHRP-6诱导CREB磷酸化呈时间依赖性。抑制PKC,特别是基因沉默PKCσ减弱了GHRP-6诱导的CREB磷酸化和GH分泌。并且,GHRP-6可以诱导PKCσ活化。
结论PKC(特别是PKCσ)参与了GHRP-6诱导的CREB磷酸化和GH分泌,将PKC信号通路和PKA信号通路连接了起来。
目的研究生长激素释放肽-6(GHRP-6)与其受体(GHS-R)结合后细胞内的信号传导机制,检测信号传导通路中PKC的下游分子。方法首先利用腺苷酸环化酶(AC)的抑制剂MDL-12,330A以不同浓度干预GH3细胞2小时,然后给予GHRP-6(100nM)刺激细胞。应用cAMP-酶联免疫吸附试验(cAMP-ELISA)检测AC被抑制后cAMP的生成水平。同时应用GH-ELISA检测AC被抑制后,GHRP-6诱导的GH分泌水平的变化,应用Western blot检测AC被抑制后,GHRP-6诱导的CREB磷酸化水平的变化。
结果MDL-12,330A可以明显抑制基础的和GHRP-6诱导的cAMP生成(P＜0.01)；AC被MDL-12,330A抑制后,GHRP-6诱导的GH分泌水平和CREB磷酸化水平明显减弱(P<0.01)。
结论GHRP-6诱导垂体生长激素腺瘤生长激素分泌和CREB磷酸化需依赖腺苷酸环化酶的活化。
目的检测一氧化氮(nitric oxide,NO)对ghrelin诱导的大鼠GH3细胞的生长激素(GH)分泌和细胞增殖的影响,探讨NO的作用机制。
方法首先检测ghrelin在不同浓度和不同作用时间时对GH3细胞GH分泌和增殖的影响；然后预先用SNAP (NO的供体)和NAME (NO合成酶的抑制剂)干预细胞后,检测NO对ghrelin诱导的GH分泌和细胞增殖的影响；用酶联免疫吸附试验(ELISA)方法检测GH水平,MTT法检测细胞增殖,Western免疫印迹法细胞内信号通路蛋白的活性变化。
结果ghrelin刺激GH3细胞分泌GH呈时间和浓度依赖性(P<0.01),ghrelin明显刺激GH3细胞的增殖(P<0.05);SNAP可抑制基础的和ghrelin刺激的GH分泌(P＜0.05),对细胞增殖也有明显影响(P<0.05),而NAME对GH的分泌和细胞增殖无影响；ghrelin可诱导细胞外信号调节激酶(ERK)的活化,SNAP可以抑制这种效应。
结论ghrelin促进GH3细胞GH分泌和细胞增殖,NO可以抑制些种效应,其机制可能阻断了ghrelin激活的ERK信号通路。
Objective To study the mechanism of GHRP-6-activated signal transduction by binding to growth hormone secretagogues receptor (GHS-R). Explore the protein kinase C (PKC) isoforms which play the critical role in the signaling pathways.
Methods Firstly, measure the effect of GHRP-6 on growth hormone (GH) release and cAMP-responsive element-binding protein (CREB) phosphorylation. Secondly, detect the PKC isoforms which mediated these responses of GHRP-6:GH3 cells were treated with PKC activator (phorbol ester, PMA) or inhibitors (G66983 and rottlerin), and a dominant negative mutant of PKCσwas transfected into the cells by lipo2000. Genomic sequence of this isoform gene was retrieved from Genebank. The siRNA was synthesized by Company. Measure the expression of this isoform to detect the transfection efficiency. Measure the effect of GHRP-6 on GH release and CREB phosphorylation after transfection. Examine this isoform activity after treatment of GHRP-6 to verify the result.
Results GHRP-6 stimulated GH secretion in both time-and dose-dependent manner (P<0.05) and enhanced the effect of GHRH on GH secretion (P< 0.05).This study provided the first evidence that GHRP-6 could stimulate CREB phosphorylation. These responses of GHRP-6 were reduced by the PKC inhibitors and knockdown of PKCσ. Moreover, PKCσcould be activated by GHRP-6.
Conclusion PKC, especially PKCσ, mediated CREB phosphorylation and GH secretion induced by GHRP-6 in GH3 cells.
Objective To study the mechanism of GHRP-6-activated signal transduction by binding to growth hormone secretagogues receptor (GHS-R). Explore the downstream mediatory molecules of PKC in the signaling pathways.
Methods Firstly, GH3 cells were treated with adenylate cyclase (AC) inhibitor, MDL-12,330A, in different dose for 2 h. Then, cells were treated with GHRP-6 (100 nM). Measure the cell cAMP level after AC inhibition by using cAMP-enzyme-linked immunosorbent assay (ELISA) kit. Examine the effect of GHRP-6 on GH secretion after AC inhibition by using GH-ELISA kit. Western blot was used to detect the effect of GHRP-6 on CREB phosphorylation.
Results MDL-12,330A reduced basal and GHRP-6-induced cAMP production (P< 0.01). Inhibition on AC decreased CREB phosphorylation and GH secretion induced by GHRP-6 (P< 0.01).
Conclusion GHRP-6-induced CREB phosphorylation and growth hormone secretion depends on AC activation in GH3 cells.
Objective Measure the effects of ghrelin and Nitric Oxide (NO) on growth hormone (GH) secretion and cell proliferation in rat GH3 cells and explore the possible mechanism of these responses.
Methods GH3 cells were incubated by ghrelin on different concentrations or for different times to measure the effect of ghrelin on GH secretion; then, to determine the effect of ghrelin on GH secretion and cell proliferation after SNAP and NAME treatment; GH levels in the cells medium were determined by enzyme linked immunosorbent assay (ELISA) kit. The cell proliferation rate was measured by MTT and the expression of cells proteins were examined by Western blotting.
Results Ghrelin induced GH secretion in both time-and dose-dependent manner (P< 0.01) and ghrelin induced cell proliferation (P< 0.05); the stimulatory effects of ghrelin were reduced by SNAP (P< 0.05) but NAME. SNAP could also inhibit the basal GH secretion and cell proliferation (P< 0.05); ghrelin activated extracellular signal-regulated kinase (ERK) signaling pathway and SNAP blocked this pathway.
Conclusion Nitric oxide blocks growth hormone secretion and cell proliferation induced by ghrelin in GH3 cells via blocking ERK signaling pathway.
方法首先检测GHRP-6对大鼠垂体GH腺瘤细胞系GH3细胞生长激素(GH)分泌和cAMP反应元件结合蛋白(CREB)磷酸化的调节作用。然后对GHRP-6诱导激活的PKC亚型进行初步筛选：应用PKC广谱激动剂佛波醇酯(PMA)和两种PKC抑制剂(Go6983和rottlerin)干预GH3细胞。对初步筛选出的PKC亚型进行RNA干扰,沉默其表达,以确定该亚型的作用：根据Genebank数据库提供的基因核苷酸序列设计干扰序列,由生物公司帮助合成；利用lipo2000作为载体转染GH3细胞。转染后,应用Western blot检测该亚型的蛋白表达,以确定转染效率。同时检测基因沉默该亚型后,GHRP-6对GH分泌和CREB磷酸化的调节作用的变化。并检测GHRP-6作用后该亚型的活性。
结果GHRP-6诱导GH分泌呈时间和浓度依赖性(P<0.05),并且可以增强生长激素释放激素(GHRH)的作用(P<0.05)。GHRP-6诱导CREB磷酸化呈时间依赖性。抑制PKC,特别是基因沉默PKCσ减弱了GHRP-6诱导的CREB磷酸化和GH分泌。并且,GHRP-6可以诱导PKCσ活化。
结论PKC(特别是PKCσ)参与了GHRP-6诱导的CREB磷酸化和GH分泌,将PKC信号通路和PKA信号通路连接了起来。
目的研究生长激素释放肽-6(GHRP-6)与其受体(GHS-R)结合后细胞内的信号传导机制,检测信号传导通路中PKC的下游分子。方法首先利用腺苷酸环化酶(AC)的抑制剂MDL-12,330A以不同浓度干预GH3细胞2小时,然后给予GHRP-6(100nM)刺激细胞。应用cAMP-酶联免疫吸附试验(cAMP-ELISA)检测AC被抑制后cAMP的生成水平。同时应用GH-ELISA检测AC被抑制后,GHRP-6诱导的GH分泌水平的变化,应用Western blot检测AC被抑制后,GHRP-6诱导的CREB磷酸化水平的变化。
结果MDL-12,330A可以明显抑制基础的和GHRP-6诱导的cAMP生成(P＜0.01)；AC被MDL-12,330A抑制后,GHRP-6诱导的GH分泌水平和CREB磷酸化水平明显减弱(P<0.01)。
结论GHRP-6诱导垂体生长激素腺瘤生长激素分泌和CREB磷酸化需依赖腺苷酸环化酶的活化。
目的检测一氧化氮(nitric oxide,NO)对ghrelin诱导的大鼠GH3细胞的生长激素(GH)分泌和细胞增殖的影响,探讨NO的作用机制。
方法首先检测ghrelin在不同浓度和不同作用时间时对GH3细胞GH分泌和增殖的影响；然后预先用SNAP (NO的供体)和NAME (NO合成酶的抑制剂)干预细胞后,检测NO对ghrelin诱导的GH分泌和细胞增殖的影响；用酶联免疫吸附试验(ELISA)方法检测GH水平,MTT法检测细胞增殖,Western免疫印迹法细胞内信号通路蛋白的活性变化。
结果ghrelin刺激GH3细胞分泌GH呈时间和浓度依赖性(P<0.01),ghrelin明显刺激GH3细胞的增殖(P<0.05);SNAP可抑制基础的和ghrelin刺激的GH分泌(P＜0.05),对细胞增殖也有明显影响(P<0.05),而NAME对GH的分泌和细胞增殖无影响；ghrelin可诱导细胞外信号调节激酶(ERK)的活化,SNAP可以抑制这种效应。
结论ghrelin促进GH3细胞GH分泌和细胞增殖,NO可以抑制些种效应,其机制可能阻断了ghrelin激活的ERK信号通路。
Objective To study the mechanism of GHRP-6-activated signal transduction by binding to growth hormone secretagogues receptor (GHS-R). Explore the protein kinase C (PKC) isoforms which play the critical role in the signaling pathways.
Methods Firstly, measure the effect of GHRP-6 on growth hormone (GH) release and cAMP-responsive element-binding protein (CREB) phosphorylation. Secondly, detect the PKC isoforms which mediated these responses of GHRP-6:GH3 cells were treated with PKC activator (phorbol ester, PMA) or inhibitors (G66983 and rottlerin), and a dominant negative mutant of PKCσwas transfected into the cells by lipo2000. Genomic sequence of this isoform gene was retrieved from Genebank. The siRNA was synthesized by Company. Measure the expression of this isoform to detect the transfection efficiency. Measure the effect of GHRP-6 on GH release and CREB phosphorylation after transfection. Examine this isoform activity after treatment of GHRP-6 to verify the result.
Results GHRP-6 stimulated GH secretion in both time-and dose-dependent manner (P<0.05) and enhanced the effect of GHRH on GH secretion (P< 0.05).This study provided the first evidence that GHRP-6 could stimulate CREB phosphorylation. These responses of GHRP-6 were reduced by the PKC inhibitors and knockdown of PKCσ. Moreover, PKCσcould be activated by GHRP-6.
Conclusion PKC, especially PKCσ, mediated CREB phosphorylation and GH secretion induced by GHRP-6 in GH3 cells.
Objective To study the mechanism of GHRP-6-activated signal transduction by binding to growth hormone secretagogues receptor (GHS-R). Explore the downstream mediatory molecules of PKC in the signaling pathways.
Methods Firstly, GH3 cells were treated with adenylate cyclase (AC) inhibitor, MDL-12,330A, in different dose for 2 h. Then, cells were treated with GHRP-6 (100 nM). Measure the cell cAMP level after AC inhibition by using cAMP-enzyme-linked immunosorbent assay (ELISA) kit. Examine the effect of GHRP-6 on GH secretion after AC inhibition by using GH-ELISA kit. Western blot was used to detect the effect of GHRP-6 on CREB phosphorylation.
Results MDL-12,330A reduced basal and GHRP-6-induced cAMP production (P< 0.01). Inhibition on AC decreased CREB phosphorylation and GH secretion induced by GHRP-6 (P< 0.01).
Conclusion GHRP-6-induced CREB phosphorylation and growth hormone secretion depends on AC activation in GH3 cells.
Objective Measure the effects of ghrelin and Nitric Oxide (NO) on growth hormone (GH) secretion and cell proliferation in rat GH3 cells and explore the possible mechanism of these responses.
Methods GH3 cells were incubated by ghrelin on different concentrations or for different times to measure the effect of ghrelin on GH secretion; then, to determine the effect of ghrelin on GH secretion and cell proliferation after SNAP and NAME treatment; GH levels in the cells medium were determined by enzyme linked immunosorbent assay (ELISA) kit. The cell proliferation rate was measured by MTT and the expression of cells proteins were examined by Western blotting.
Results Ghrelin induced GH secretion in both time-and dose-dependent manner (P< 0.01) and ghrelin induced cell proliferation (P< 0.05); the stimulatory effects of ghrelin were reduced by SNAP (P< 0.05) but NAME. SNAP could also inhibit the basal GH secretion and cell proliferation (P< 0.05); ghrelin activated extracellular signal-regulated kinase (ERK) signaling pathway and SNAP blocked this pathway.
Conclusion Nitric oxide blocks growth hormone secretion and cell proliferation induced by ghrelin in GH3 cells via blocking ERK signaling pathway.
引文
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[1]Frohman LA, Kineman RD, Kamegai J, et al. Secretagogues and the somatotrope: signaling and proliferation [J]. Recent Prog Horm Res,2000,55:269-290.
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[4]Frutos MG, Cacicedo L, Mendez CF, et al. Pituitary alterations involved in the decline of growth hormone gene expression in the pituitary of aging rats [J]. J Gerontol A Biol Sci Med Sci,2007,62(6):585-597.
[5]Mayo KE, Godfrey PA, Suhr ST, et al. Growth hormone-releasing hormone:synthesis and signaling [J]. Recent Proq Horm Res 1995,50:35-73.
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[2]张华楸,王雄伟,范月超 等.“交叉通讯”在人垂体生长激素腺瘤激素分泌中的调控作用研究[J].微循环学杂志,2005,15(2)：11-14.
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[4]Chen HP, Zhang L, Xu BH, et al. Nitric oxide stimulates embryonic somatotroph differentiation and growth hormone mRNA and protein expression through a cyclic guanosine monophosphate-independent mechanism [J]. Tissue Cell,2009,41(2): 133-140.
[5]Bredt DS, Hwang PM, Snyder SH. Localization of nitric oxide synthase indicating a neural role for nitric oxide [J]. Nature,1990,347(6295):768-770.
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