AIM: To investigate the inhibitory role and the underlying mechanisms of sorafenib on signal transducer and activator of transcription 3 (STAT3) activity in hepatocellular carcinoma (HCC).METHODS: Human and rat HCC ce...AIM: To investigate the inhibitory role and the underlying mechanisms of sorafenib on signal transducer and activator of transcription 3 (STAT3) activity in hepatocellular carcinoma (HCC).METHODS: Human and rat HCC cell lines were treated with sorafenib. Proliferation and STAT3 dephosphorylation were assessed. Potential molecular mechanisms of STAT3 pathway inhibition by sorafenib were evaluated. In vivo antitumor action and STAT3 inhibition were investigated in an immunocompetent orthotopic rat HCC model.RESULTS: Sorafenib decreased STAT3 phosphorylationat the tyrosine and serine residues (Y705 and S727), but did not affect Janus kinase 2 (JAK2) and phosphatase shatterproof 2 (SHP2), which is associated with growth inhibition in HCC cells. Dephosphorylation of S727 was associated with attenuated extracellular signal-regulated kinase (ERK) phosphorylation, similar to the effects of a mitogen-activated protein kinase (MEK) inhibitor U0126, suggesting that sorafenib induced S727 dephosphorylation by inhibiting MEK/ERK signaling. Meanwhile, sorafenib could also inhibit Akt phosphorylation, and both the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and Akt knockdown resulted in Y705 dephosphorylation, indicating that Y705 dephosphorylation by sorafenib was mediated by inhibiting the PI3K/Akt pathway. Finally, in the rat HCC model, sorafenib signifi cantly inhibited STAT3 activity, reducing tumor growth and metastasis.CONCLUSION: Sorafenib inhibits growth and metastasis of HCC in part by blocking the MEK/ERK/STAT3 and PI3K/Akt/STAT3 signaling pathways, but independent of JAK2 and SHP2 activation.展开更多
通过测定脑缺血再灌注时海马中半胱天冬酶-3酶原(procaspase-3)的表达变化,从细胞凋亡的角度探讨脑缺血再灌注损伤的分子生物学机制及procaspase-3的活化机制.将C57BL/6N小鼠随机分为假手术组(正常对照组)、缺血再灌注组(I/R组),后者夹...通过测定脑缺血再灌注时海马中半胱天冬酶-3酶原(procaspase-3)的表达变化,从细胞凋亡的角度探讨脑缺血再灌注损伤的分子生物学机制及procaspase-3的活化机制.将C57BL/6N小鼠随机分为假手术组(正常对照组)、缺血再灌注组(I/R组),后者夹闭双侧颈总动脉20 min后再通血流,建立前脑缺血再灌注模型,分别于再灌注6 h、12 h、24 h和48 h取海马.采用蛋白免疫印迹(Western blotting)方法检测海马中procaspase-3的表达变化.结果显示,12 h I/R及24 h I/R组海马中总procaspase-3水平与假手术组相比有明显升高,且差异有统计学意义(P<0.05);24 h I/R组海马中去磷酸化水平与假手术组相比有明显升高,且差异有统计学意义(P<0.05);而各组procaspase-3磷酸化水平与假手术组相比差异无统计学意义.结果提示,脑缺血再灌注损伤诱发procaspase-3表达增加;其中procaspase-3去磷酸化水平高明显,提示脑缺血再灌注损伤可能诱发procaspase-3去磷酸化,继而促进procaspase-3转化为活性形式.展开更多
植物在生长发育的过程中要面对一系列非生物和生物胁迫的侵害,为了应对这些胁迫,植物进化出了复杂的调控机制。蛋白质的翻译后修饰是其中一种重要的调节方式,包括蛋白激酶介导的磷酸化和蛋白磷酸酶介导的去磷酸化。PP2Cs(protein phosph...植物在生长发育的过程中要面对一系列非生物和生物胁迫的侵害,为了应对这些胁迫,植物进化出了复杂的调控机制。蛋白质的翻译后修饰是其中一种重要的调节方式,包括蛋白激酶介导的磷酸化和蛋白磷酸酶介导的去磷酸化。PP2Cs(protein phosphatases type 2C)是植物中最大的蛋白磷酸酶家族,可以在多个信号级联反应中发挥作用,在干旱和盐碱胁迫中,PP2Cs通过依赖和不依赖ABA两种方式发挥负调控作用;在低温胁迫中,PP2Cs促进OST1的活性赋予植物低温耐受性;在营养胁迫中,PP2C参与调控氮元素和钾元素的吸收。此外,PP2Cs也参与了植物对虫害和病原菌的调控。探究PP2Cs调控不同胁迫的分子机制,对提高植物的抗逆性和作物产量具有重要意义。展开更多
基金Supported by Grants from the China 863 Project, No. 2007A-A02Z479the National Natural Science Foundation of China, No. 30972949 and 30901432+1 种基金Shanghai Rising-Star Program, No. 10QA1401300Research Fund for the Doctoral Program of Higher Education of China, No. 20090071120026
文摘AIM: To investigate the inhibitory role and the underlying mechanisms of sorafenib on signal transducer and activator of transcription 3 (STAT3) activity in hepatocellular carcinoma (HCC).METHODS: Human and rat HCC cell lines were treated with sorafenib. Proliferation and STAT3 dephosphorylation were assessed. Potential molecular mechanisms of STAT3 pathway inhibition by sorafenib were evaluated. In vivo antitumor action and STAT3 inhibition were investigated in an immunocompetent orthotopic rat HCC model.RESULTS: Sorafenib decreased STAT3 phosphorylationat the tyrosine and serine residues (Y705 and S727), but did not affect Janus kinase 2 (JAK2) and phosphatase shatterproof 2 (SHP2), which is associated with growth inhibition in HCC cells. Dephosphorylation of S727 was associated with attenuated extracellular signal-regulated kinase (ERK) phosphorylation, similar to the effects of a mitogen-activated protein kinase (MEK) inhibitor U0126, suggesting that sorafenib induced S727 dephosphorylation by inhibiting MEK/ERK signaling. Meanwhile, sorafenib could also inhibit Akt phosphorylation, and both the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and Akt knockdown resulted in Y705 dephosphorylation, indicating that Y705 dephosphorylation by sorafenib was mediated by inhibiting the PI3K/Akt pathway. Finally, in the rat HCC model, sorafenib signifi cantly inhibited STAT3 activity, reducing tumor growth and metastasis.CONCLUSION: Sorafenib inhibits growth and metastasis of HCC in part by blocking the MEK/ERK/STAT3 and PI3K/Akt/STAT3 signaling pathways, but independent of JAK2 and SHP2 activation.
文摘通过测定脑缺血再灌注时海马中半胱天冬酶-3酶原(procaspase-3)的表达变化,从细胞凋亡的角度探讨脑缺血再灌注损伤的分子生物学机制及procaspase-3的活化机制.将C57BL/6N小鼠随机分为假手术组(正常对照组)、缺血再灌注组(I/R组),后者夹闭双侧颈总动脉20 min后再通血流,建立前脑缺血再灌注模型,分别于再灌注6 h、12 h、24 h和48 h取海马.采用蛋白免疫印迹(Western blotting)方法检测海马中procaspase-3的表达变化.结果显示,12 h I/R及24 h I/R组海马中总procaspase-3水平与假手术组相比有明显升高,且差异有统计学意义(P<0.05);24 h I/R组海马中去磷酸化水平与假手术组相比有明显升高,且差异有统计学意义(P<0.05);而各组procaspase-3磷酸化水平与假手术组相比差异无统计学意义.结果提示,脑缺血再灌注损伤诱发procaspase-3表达增加;其中procaspase-3去磷酸化水平高明显,提示脑缺血再灌注损伤可能诱发procaspase-3去磷酸化,继而促进procaspase-3转化为活性形式.
文摘植物在生长发育的过程中要面对一系列非生物和生物胁迫的侵害,为了应对这些胁迫,植物进化出了复杂的调控机制。蛋白质的翻译后修饰是其中一种重要的调节方式,包括蛋白激酶介导的磷酸化和蛋白磷酸酶介导的去磷酸化。PP2Cs(protein phosphatases type 2C)是植物中最大的蛋白磷酸酶家族,可以在多个信号级联反应中发挥作用,在干旱和盐碱胁迫中,PP2Cs通过依赖和不依赖ABA两种方式发挥负调控作用;在低温胁迫中,PP2Cs促进OST1的活性赋予植物低温耐受性;在营养胁迫中,PP2C参与调控氮元素和钾元素的吸收。此外,PP2Cs也参与了植物对虫害和病原菌的调控。探究PP2Cs调控不同胁迫的分子机制,对提高植物的抗逆性和作物产量具有重要意义。
