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The KLF family of transcriptional regulators in cardiomyocyte proliferation and differentiation.

机译:转录因子KLF家族在心肌细胞的增殖和分化中的作用。

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摘要

Unlike other organs, the adult heart has limited regenerative potential owing to the inability of postnatal cardiomyocytes to undergo proliferative growth. As a result, ischemic heart disease continues to be a major cause of morbidity and mortality worldwide. Elucidating the molecular pathways of cardiomyocyte differentiation and proliferation holds great promise for human health. In a recent paper we employed a multidisciplinary approach to identify a novel pathway required for cardiomyocyte growth and differentiation. Starting with the dissection of a new regulatory sequence required for cardiac specific expression, we identified the cognate DNA binding protein as KLF13, a tissue-restricted member of the newly identified KLF family of zinc-finger proteins. We took advantage of the ease in manipulating Xenopus embryos to genetically alter KLF13 levels thus demonstrating a requirement for KLF13 in cardiac progenitor cell proliferation and heart morphogenesis. Furthermore, we combined biochemical approaches with genetic manipulations in Xenopus to show that KLF13 is a GATA4 interacting protein and a genetic modifier of GATA4 function. Cyclin D1 was identified as a direct transcriptional target for KLF13 that may account for the proliferation defects observed in embryos with downregulated KLF13 levels. Thus, tissue-specific regulators of the cell cycle may be potential congenital heart disease causing genes in humans.
机译:与其他器官不同,由于产后心肌细胞无法进行增殖性生长,因此成年心脏的再生潜力有限。结果,缺血性心脏病仍然是全世界发病率和死亡率的主要原因。阐明心肌细胞分化和增殖的分子途径对人类健康具有广阔的前景。在最近的论文中,我们采用了多学科的方法来确定心肌细胞生长和分化所需的新途径。从解剖心脏特异性表达所需的新调控序列开始,我们将同源DNA结合蛋白鉴定为KLF13,这是新鉴定的锌指蛋白KLF家族的组织限制性成员。我们利用操作非洲爪蟾胚胎的便利性来遗传改变KLF13的水平,从而证明在心脏祖细胞增殖和心脏形态发生中需要KLF13。此外,我们将生物化学方法与非洲爪蟾的遗传操作相结合,显示KLF13是GATA4相互作用蛋白和GATA4功能的遗传修饰剂。细胞周期蛋白D1被确定为KLF13的直接转录靶标,这可能解释了KLF13水平下调的胚胎中观察到的增殖缺陷。因此,细胞周期的组织特异性调节剂可能是人类潜在的先天性心脏病基因。

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