Myotonic dystrophy type 1(DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysre...Myotonic dystrophy type 1(DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysregulation of ryanodine receptor 1(RYR1), sarcoplasmatic/endoplasmatic Ca^2+-ATPase(SERCA) and α1 S subunit of voltage-gated Ca^2+ channels(Cav1.1) is related to Ca^2+ homeostasis and excitation-contraction coupling impairment. Though no pharmacological treatment for DM1 exists, aberrant splicing correction represents one major therapeutic target for this disease. Resveratrol(RES, 3,5,4′-trihydroxy-trans-stilbene) is a promising pharmacological tools for DM1 treatment for its ability to directly bind the DNA and RNA influencing gene expression and alternative splicing. Herein, we analyzed the therapeutic effects of RES in DM1 myotubes in a pilot study including cultured myotubes from two DM1 patients and two healthy controls. Our results indicated that RES treatment corrected the aberrant splicing of RYR1, and this event appeared associated with restoring of depolarization-induced Ca^2+ release from RYR1 dependent on the electro-mechanical coupling between RYR1 and Cav1.1. Interestingly, immunoblotting studies showed that RES treatment was associated with a reduction in the levels of CUGBP Elav-like family member 1, while RYR1, Cav1.1 and SERCA1 protein levels were unchanged. Finally, RES treatment did not induce any major changes either in the amount of ribonuclear foci or sequestration of muscleblind-like splicing regulator 1. Overall, the results of this pilot study would support RES as an attractive compound for future clinical trials in DM1. Ethical approval was obtained from the Ethical Committee of IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy(rs9879/14) on May 20, 2014.展开更多
肌盲样蛋白1(muscle blind-like protein 1,MBNL1)是一种RNA结合蛋白,其作为前体信使RNA(precursor mRNA,pre-mRNA)的可变剪接因子,在发育过程中起调节作用,有助于对特定转录集的转录后调控。MBNL1可以影响RNA成熟和表达过程的多个步骤...肌盲样蛋白1(muscle blind-like protein 1,MBNL1)是一种RNA结合蛋白,其作为前体信使RNA(precursor mRNA,pre-mRNA)的可变剪接因子,在发育过程中起调节作用,有助于对特定转录集的转录后调控。MBNL1可以影响RNA成熟和表达过程的多个步骤,包括pre-mRNA的剪接、降解、RNA输出、稳定性维持、修饰和翻译等。MBNL1最早被认为是强直性肌营养不良发病机制的相关因子,随着研究的深入,其在多种非肿瘤性疾病以及肿瘤性疾病中的作用逐渐凸显。研究表明,MBNL1在多种疾病中表达异常,并且与恶性肿瘤如胃癌、结直肠癌、乳腺癌、前列腺癌、脑胶质瘤、肺癌、血液系统肿瘤等的发生、发展以及转移密切相关。由于细胞种类和发育环境的不同,正常细胞和肿瘤细胞中MBNL1蛋白水平的变化具有多样性。MBNL1既可作为转录激活因子促进肿瘤的发生与发展,也可作为转录阻遏因子抑制肿瘤的生长、转移等过程,在恶性肿瘤的发病过程中发挥重要作用。该文就MBNL1在肿瘤发生发展中的分子机制、生物学特性及其在不同恶性肿瘤中的表达和功能进行综述,为肿瘤的靶向治疗及预后评估提供新的研究思路。展开更多
基金supported by grants from UniversitàCattolica and Italian Ministry of Scientific Research(grant number D1-2016 to GS)
文摘Myotonic dystrophy type 1(DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysregulation of ryanodine receptor 1(RYR1), sarcoplasmatic/endoplasmatic Ca^2+-ATPase(SERCA) and α1 S subunit of voltage-gated Ca^2+ channels(Cav1.1) is related to Ca^2+ homeostasis and excitation-contraction coupling impairment. Though no pharmacological treatment for DM1 exists, aberrant splicing correction represents one major therapeutic target for this disease. Resveratrol(RES, 3,5,4′-trihydroxy-trans-stilbene) is a promising pharmacological tools for DM1 treatment for its ability to directly bind the DNA and RNA influencing gene expression and alternative splicing. Herein, we analyzed the therapeutic effects of RES in DM1 myotubes in a pilot study including cultured myotubes from two DM1 patients and two healthy controls. Our results indicated that RES treatment corrected the aberrant splicing of RYR1, and this event appeared associated with restoring of depolarization-induced Ca^2+ release from RYR1 dependent on the electro-mechanical coupling between RYR1 and Cav1.1. Interestingly, immunoblotting studies showed that RES treatment was associated with a reduction in the levels of CUGBP Elav-like family member 1, while RYR1, Cav1.1 and SERCA1 protein levels were unchanged. Finally, RES treatment did not induce any major changes either in the amount of ribonuclear foci or sequestration of muscleblind-like splicing regulator 1. Overall, the results of this pilot study would support RES as an attractive compound for future clinical trials in DM1. Ethical approval was obtained from the Ethical Committee of IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy(rs9879/14) on May 20, 2014.
文摘肌盲样蛋白1(muscle blind-like protein 1,MBNL1)是一种RNA结合蛋白,其作为前体信使RNA(precursor mRNA,pre-mRNA)的可变剪接因子,在发育过程中起调节作用,有助于对特定转录集的转录后调控。MBNL1可以影响RNA成熟和表达过程的多个步骤,包括pre-mRNA的剪接、降解、RNA输出、稳定性维持、修饰和翻译等。MBNL1最早被认为是强直性肌营养不良发病机制的相关因子,随着研究的深入,其在多种非肿瘤性疾病以及肿瘤性疾病中的作用逐渐凸显。研究表明,MBNL1在多种疾病中表达异常,并且与恶性肿瘤如胃癌、结直肠癌、乳腺癌、前列腺癌、脑胶质瘤、肺癌、血液系统肿瘤等的发生、发展以及转移密切相关。由于细胞种类和发育环境的不同,正常细胞和肿瘤细胞中MBNL1蛋白水平的变化具有多样性。MBNL1既可作为转录激活因子促进肿瘤的发生与发展,也可作为转录阻遏因子抑制肿瘤的生长、转移等过程,在恶性肿瘤的发病过程中发挥重要作用。该文就MBNL1在肿瘤发生发展中的分子机制、生物学特性及其在不同恶性肿瘤中的表达和功能进行综述,为肿瘤的靶向治疗及预后评估提供新的研究思路。
