Regulation of c-Myc mRNA by L11 in Response to UV and Gamma irradiation
Annual rept. 20 Sep 2010-19 Sep 2011
OREGON HEALTH AND SCIENCE UNIV PORTLAND
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In this funding period, we have discovered that L11 downregulates c-myc mRNA through a mircoRNA-mediated pathway. L11 binds to c-myc mRNA at its 3-untranslated region 3-UTR, the core component of microRNA-induced silencing complex miRISC 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 the miR-24-mediated c-myc mRNA decay. We further show that ribosome-free L11 binds to c-myc mRNA in the cytoplasm and this binding is enhanced in response to ribosomal stress. Meanwhile, we found that c-myc is also down-regulated in response to DNA damage including UV and gamma-irradiation gamma-IR in an L11-dependent manner. Altogether, 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 stress.
- Medicine and Medical Research