Division of Immunology, Infection and Inflammatory Disease, King's College London, London, United Kingdom.
PLoS One. 2012;7(12):e52187. doi: 10.1371/journal.pone.0052187. Epub 2012 Dec 20.
The ZFP36/Tis11 family of zinc-finger proteins regulate cellular processes by binding to adenine uridine rich elements in the 3' untranslated regions of various mRNAs and promoting their degradation. We show here that ZFP36L1 expression is largely extinguished during the transition from B cells to plasma cells, in a reciprocal pattern to that of ZFP36 and the plasma cell transcription factor, BLIMP1. Enforced expression of ZFP36L1 in the mouse BCL1 cell line blocked cytokine-induced differentiation while shRNA-mediated knock-down enhanced differentiation. Reconstruction of regulatory networks from microarray gene expression data using the ARACNe algorithm identified candidate mRNA targets for ZFP36L1 including BLIMP1. Genes that displayed down-regulation in plasma cells were significantly over-represented (P = <0.0001) in a set of previously validated ZFP36 targets suggesting that ZFP36L1 and ZFP36 target distinct sets of mRNAs during plasmacytoid differentiation. ShRNA-mediated knock-down of ZFP36L1 in BCL1 cells led to an increase in levels of BLIMP1 mRNA and protein, but not for mRNAs of other transcription factors that regulate plasmacytoid differentiation (xbp1, irf4, bcl6). Finally, ZFP36L1 significantly reduced the activity of a BLIMP1 3' untranslated region-driven luciferase reporter. Taken together, these findings suggest that ZFP36L1 negatively regulates plasmacytoid differentiation, at least in part, by targeting the expression of BLIMP1.
ZFP36/Tis11 家族的锌指蛋白通过结合各种 mRNA 的 3'非翻译区中的腺嘌呤尿嘧啶丰富元件并促进其降解，从而调节细胞过程。我们在这里表明，ZFP36L1 的表达在 B 细胞向浆细胞转化过程中基本消失，与 ZFP36 和浆细胞转录因子 BLIMP1 的表达模式相反。在小鼠 BCL1 细胞系中强制表达 ZFP36L1 可阻断细胞因子诱导的分化，而 shRNA 介导的敲低则增强分化。使用 ARACNe 算法从微阵列基因表达数据重建调控网络，鉴定了 ZFP36L1 的候选 mRNA 靶标，包括 BLIMP1。在一组先前验证的 ZFP36 靶标中，浆细胞中下调的基因显著过表达（P<0.0001），这表明 ZFP36L1 和 ZFP36 在浆细胞分化过程中靶向不同的 mRNA 集。在 BCL1 细胞中，shRNA 介导的 ZFP36L1 敲低导致 BLIMP1 mRNA 和蛋白水平增加，但调节浆细胞分化的其他转录因子（xbp1、irf4、bcl6）的 mRNA 水平没有增加。最后，ZFP36L1 显著降低了 BLIMP1 3'非翻译区驱动的荧光素酶报告基因的活性。总之，这些发现表明 ZFP36L1 通过靶向 BLIMP1 的表达来负调控浆细胞分化，至少部分如此。
