Essential role of the RNA-binding protein HuR in progenitor cell survival in mice
Essential role of the RNA-binding protein HuR in progenitor cell survival in mice
复制标题
DOI：
10.1172/jci38263
复制
发表时间：
2009-12-01
影响因子：
15.9
通讯作者：
Hla, Timothy
中科院分区：
文献类型：
--
作者：
Ghosh, Mallika;Aguila, Hector Leonardo;Hla, Timothy
RNA结合蛋白HuR（也称为ELAV 1）与mRNA的3 '-非翻译区结合，并调节转录物的稳定性和翻译。然而，HuR的体内功能还不清楚。在这里，我们报告说，鼠HuR是必不可少的生命;出生后的全球删除Elavl 1诱导造血器官萎缩，肠绒毛的广泛损失，梗阻性小肠结肠炎，并在10天内致死。Elavl 1缺失后，骨髓、胸腺和肠中的祖细胞发生凋亡，而静止干细胞和分化细胞不受影响。造血祖细胞的存活缺陷是细胞内在的，因为Elavl 1（-/-）BM的移植导致造血重建受损，但不引起致死性。随着HuR水平的下降，在祖细胞中诱导了对细胞死亡至关重要的p53及其下游效应物的表达。在小鼠胚胎成纤维细胞中，HuR结合并稳定Mdm 2的mRNA，Mdm 2是p53的关键负调节因子。此外，Elavl 1（-/-）细胞中Mdm 2的表达恢复了细胞存活，表明HuR在祖细胞中保持p53水平，从而促进细胞存活。我们认为，这种由HuR在祖细胞中调节细胞应激反应的新方法可能在细胞毒性抗癌疗法以及干细胞移植疗法中得到利用。
The RNA-binding protein HuR (also known as ELAV1) binds to the 3'-untranslated region of mRNAs and regulates transcript stability and translation. However, the in vivo functions of HuR are not well understood. Here, we report that murine HuR is essential for life; postnatal global deletion of Elavl1 induced atrophy of hematopoietic organs, extensive loss of intestinal villi, obstructive enterocolitis, and lethality within 10 days. Upon Elavl1 deletion, progenitor cells in the BM, thymus, and intestine underwent apoptosis, whereas quiescent stem cells and differentiated cells were unaffected. The survival defect of hematopoietic progenitor cells was cell intrinsic, as transplant of Elavl1(-/-) BM led to compromised hematopoietic reconstitution but did not cause lethality. Expression of p53 and its downstream effectors critical for cell death were induced in progenitor cells as HuR levels declined. In mouse embryonic fibroblasts, HuR bound to and stabilized the mRNA for Mdm2, a critical negative regulator of p53. Furthermore, cell survival was restored by expression of Mdm2 in Elavl1(-/-) cells, suggesting that HuR keeps p53 levels in check in progenitor cells and thereby promotes cell survival. This regulation of cell stress response by HuR in progenitor cells, which we believe to be novel, could potentially be exploited in cytotoxic anticancer therapies as well as stem cell transplant therapy.