Ribosomal Protein L11 Recruits miR-24/miRISC To Repress c-Myc Expression in Response to Ribosomal Stress
Ribosomal Protein L11 Recruits miR-24/miRISC To Repress c-Myc Expression in Response to Ribosomal Stress
复制标题
DOI：
10.1128/mcb.05810-11
复制
发表时间：
2011-10-01
影响因子：
5.3
通讯作者：
Dai, Mu-Shui
中科院分区：
文献类型：
--
作者：
Challagundla, Kishore B.;Sun, Xiao-Xin;Dai, Mu-Shui
c-Myc通过增强核糖体生物合成和翻译促进细胞生长。c-Myc的表达失调和异常的核糖体生物合成和翻译有助于肿瘤发生。因此，c-Myc和核糖体生物合成之间的良好协调对于正常细胞内稳态至关重要。在这里，我们表明，核糖体蛋白L11调节c-myc mRNA的营业额。L11在其3'非翻译区（3' -UTR）（microRNA诱导的沉默复合物（miRISC）argonaute 2（Ago 2）的核心组分）以及miR-24处与c-myc mRNA结合，导致c-myc mRNA减少。L11的敲低显著增加了c-myc mRNA的水平和稳定性。Ago 2的消融消除了L11介导的c-myc mRNA的减少，而L11的敲低挽救了miR-24介导的c-myc mRNA的衰减。有趣的是，处理细胞与核糖体应激诱导剂放线菌素D或5-氟尿嘧啶显着降低c-myc mRNA水平的L11和Ago 2依赖的方式。两种处理均增强了L11与Ago 2、miR-24和c-myc mRNA的结合。我们进一步表明，核糖体自由L11结合到c-myc mRNA在细胞质中，这种结合被放线菌素D处理增强。总之，我们的研究结果确定了一种新的调控模式，其中L11在控制c-myc mRNA周转中起着关键作用，通过招募miRISC响应核糖体应激。
c-Myc promotes cell growth by enhancing ribosomal biogenesis and translation. Deregulated expression of c-Myc and aberrant ribosomal biogenesis and translation contribute to tumorigenesis. Thus, a fine coordination between c-Myc and ribosomal biogenesis is vital for normal cell homeostasis. Here, we show that ribosomal protein L11 regulates c-myc mRNA turnover. L11 binds to c-myc mRNA at its 3' untranslated region (3' -UTR), the core component of microRNA-induced silencing complex (miRISC) argonaute 2 (Ago2), as well as miR-24, leading to c-myc mRNA reduction. Knockdown of L11 drastically increases the levels and stability of c-myc mRNA. Ablation of Ago2 abrogated the L11-mediated reduction of c-myc mRNA, whereas knockdown of L11 rescued miR-24-mediated c-myc mRNA decay. Interestingly, treatment of cells with the ribosomal stress-inducing agent actinomycin D or 5-fluorouracil significantly decreased the c-myc mRNA levels in an L11- and Ago2-dependent manner. Both treatments enhanced the association of L11 with Ago2, miR-24, and c-myc mRNA. We further show that ribosome-free L11 binds to c-myc mRNA in the cytoplasm and that this binding is enhanced by actinomycin D treatment. Together, our results identify a novel regulatory paradigm wherein L11 plays a critical role in controlling c-myc mRNA turnover via recruiting miRISC in response to ribosomal stress.