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首页> 外文期刊>Biology Open >A feedback mechanism between PLD and deadenylase PARN for the shortening of eukaryotic poly(A) mRNA tails that is deregulated in cancer cells
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A feedback mechanism between PLD and deadenylase PARN for the shortening of eukaryotic poly(A) mRNA tails that is deregulated in cancer cells

机译：PLD和腺苷酸酶PARN之间的反馈机制可缩短在癌细胞中失控的真核poly（A）mRNA尾巴

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The removal of mRNA transcript poly(A) tails by 3′→5′ exonucleases is the rate-limiting step in mRNA decay in eukaryotes. Known cellular deadenylases are the CCR4-NOT and PAN complexes, and poly(A)-specific ribonuclease (PARN). The physiological roles and regulation for PARN is beginning to be elucidated. Since phospholipase D (PLD2 isoform) gene expression is upregulated in breast cancer cells and PARN is downregulated, we examined whether a signaling connection existed between these two enzymes. Silencing PARN with siRNA led to an increase in PLD2 protein, whereas overexpression of PARN had the opposite effect. Overexpression of PLD2, however, led to an increase in PARN expression. Thus, PARN downregulates PLD2 whereas PLD2 upregulates PARN. Co-expression of both PARN and PLD2 mimicked this pattern in non-cancerous cells (COS-7 fibroblasts) but, surprisingly, not in breast cancer MCF-7 cells, where PARN switches from inhibition to activation of PLD2 gene and protein expression. Between 30 and 300?nM phosphatidic acid (PA), the product of PLD enzymatic reaction, added exogenously to culture cells had a stabilizing role of both PARN and PLD2 mRNA decay. Lastly, by immunofluorescence microscopy, we observed an intracellular co-localization of PA-loaded vesicles (0.1-1?nm) and PARN. In summary, we report for the first time the involvement of a phospholipase (PLD2) and PA in mediating PARN-induced eukaryotic mRNA decay and the crosstalk between the two enzymes that is deregulated in breast cancer cells.
机译：3'→5'核酸外切酶去除mRNA转录物poly（A）尾巴是真核生物mRNA衰变的限速步骤。已知的细胞脱烯基酶是CCR4-NOT和PAN复合物，以及聚（A）特异性核糖核酸酶（PARN）。 PARN的生理作用和调节作用已经开始阐明。由于磷脂酶D（PLD2亚型）基因表达在乳腺癌细胞中被上调，而PARN被下调，因此我们检查了这两种酶之间是否存在信号连接。用siRNA沉默PARN会导致PLD2蛋白增加，而PARN的过表达则相反。但是，PLD2的过表达导致PARN表达增加。因此，PARN下调PLD2，而PLD2上调PARN。在非癌细胞（COS-7成纤维细胞）中，PARN和PLD2的共表达模仿了这种模式，但是令人惊讶的是，在乳腺癌MCF-7细胞中，PARN从抑制转变为激活PLD2基因和蛋白质表达，这一点令人惊讶。在30至300nM的磷脂酶（PAD）酶促反应产物中，外源添加到培养细胞中对PARN和PLD2 mRNA的衰变具有稳定作用。最后，通过免疫荧光显微镜，我们观察到了PA负载的囊泡（0.1-1？nm）和PARN在细胞内的共定位。总而言之，我们首次报道了磷脂酶（PLD2）和PA在介导PARN诱导的真核mRNA衰变以及在乳腺癌细胞中被放松调节的两种酶之间的串扰中的参与。

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