Abstract：
The tumor suppressor p53 has been implicated in the pathogenesis of liver fibrosis. HERC5-mediated posttranslational ISG modification of the p53 protein is critical for controlling its activity. Here, we demonstrated that the expression of HERC5 and ISG15 is highly elevated, whereas p53 is downregulated, in fibrotic liver tissues of mice and transforming growth factor-β1 (TGF-β1)-induced LX2 cells. HERC5 siRNA clearly increased the protein expression of p53, but the mRNA expression of p53 was not obviously changed. The inhibition of lincRNA-ROR (ROR) downregulated HERC5 expression and elevated p53 expression in TGF-β1-stimulated LX-2 cells. Furthermore, the expression of p53 was almost unchanged after TGF-β1-stimulated LX-2 cells were co-transfected with a ROR-expressing plasmid and HERC5 siRNA. We further confirmed that miR-145 is a target gene of ROR. In addition, we also showed that ROR regulates the HERC5-mediated ISGylation of p53 through mir-145/ZEB2. Together, we propose that ROR/miR-145/ZEB2 might be involved in the course of liver fibrosis by regulating ISGylation of the p53 protein.
摘要：
肿瘤抑制因子p53与肝纤维化的发病机理有关。p53蛋白的HERC5介导的翻译后ISG修饰对于控制其活性至关重要。这里,我们证明HERC5和ISG15的表达高度升高，而p53下调，在小鼠纤维化肝组织和转化生长因子-β1（TGF-β1）诱导的LX2细胞中。HERC5siRNA使p53蛋白表达明显增加,但p53mRNA表达无明显变化。在TGF-β1刺激的LX-2细胞中，抑制lincRNA-ROR（ROR）下调HERC5表达并升高p53表达。此外，在TGF-β1刺激的LX-2细胞与ROR表达质粒和HERC5siRNA共转染后,p53的表达几乎没有变化.我们进一步证实miR-145是ROR的靶基因。此外,我们还显示,ROR通过mir-145/ZEB2调节HERC5介导的p53的ISG化。一起,我们认为ROR/miR-145/ZEB2可能通过调节p53蛋白的ISGylation参与肝纤维化进程。
