MicroRNA-130a associates with ribosomal protein L11 to suppress c-Myc expression in response to UV irradiation.

Yuhuang Li,Kishore B Challagundla,Mu-Shui Dai,Xiao-Xin Sun,Qinghong Zhang

doi:10.18632/oncotarget.2728

Yuhuang Li, Kishore B Challagundla + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.2728

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Abstract

The oncoprotein c-Myc is essential for cell growth and proliferation while its deregulated overexpression is associated with most human cancers. Thus tightly regulated levels and activity of c-Myc are critical for maintaining normal cell homeostasis. c-Myc is down-regulated in response to several types of stress, including UV-induced DNA damage. Yet, mechanism underlying UV-induced c-Myc reduction is not completely understood. Here we report that L11 promotes miR-130a targeting of c-myc mRNA to repress c-Myc expression in response to UV irradiation. miR-130a targets the 3'-untranslated region (UTR) of c-myc mRNA. Overexpression of miR-130a promotes the Ago2 binding to c-myc mRNA, significantly reduces the levels of both c-Myc protein and mRNA and inhibits cell proliferation. UV treatment markedly promotes the binding of L11 to miR-130a, c-myc mRNA as well as Ago2 in cells. Inhibiting miR-130a significantly suppresses UV-mediated c-Myc reduction. We further show that L11 is relocalized from the nucleolus to the cytoplasm where it associates with c-myc mRNA upon UV treatment. Together, these results reveal a novel mechanism underlying c-Myc down-regulation in response to UV-mediated DNA damage, wherein L11 promotes miR-130a-loaded miRISC to target c-myc mRNA.

Highlights

The c-Myc oncoprotein is essential for normal cell growth and proliferation by regulating the expression of a large number of genes involved in cell cycle, apoptosis, differentiation, angiogenesis, metabolism, ribosomal biogenesis, and stem cell renewal [1,2,3]
C-Myc is tightly regulated at multiple levels [3] and these mechanisms can be disrupted in cancer cells. c-Myc transcription is transiently activated by growth factor and mitogenic stimuli and controlled by multiple promoter elements at the c-myc gene [3, 5, 6]. c-Myc translation can be regulated at both the 5’-untranslated region (UTR) and the 3’-UTR [7, 8]. c-Myc protein stability is subjected to a multitude of tight posttranslational regulation via the ubiquitin-dependent proteasome system [9,10,11]
MiR-130a was immunoprecipitated by antiFlag antibody, but not control IgG, in both 293 (Fig. 1B) and U2OS (Fig. 1C) cells, suggesting that L11 associates with miR-130a in cells

Summary

INTRODUCTION

The c-Myc oncoprotein is essential for normal cell growth and proliferation by regulating the expression of a large number of genes involved in cell cycle, apoptosis, differentiation, angiogenesis, metabolism, ribosomal biogenesis, and stem cell renewal [1,2,3]. C-Myc needs to be tightly controlled in order to coordinate with stalled cell cycle progression in response to stress. We previously found that ribosomal protein L11 (L11 thereafter) regulates c-Myc levels via miR-24mediated c-myc mRNA decay in response to ribosomal stress [22]. Disruption of the nucleolus is a common event in cells following DNA damage including UV irradiation [42], suggesting that L11 may play a role in regulating c-Myc via miRISC in response to DNA damage as well. UV damage induces the release of L11 from the nucleolus to the cytoplasm where it recruits miR-130aassociated RNA interference silencing complex (miRISC) to target c-myc mRNA at its 3’-UTR. Our results uncover a novel function of miR-130a in suppressing c-Myc in response to DNA damage

RESULTS

DISCUSSION

EXPERIMENTAL PROCEDURES