Modulation of microRNA Processing by p53

Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Nature (Impact Factor: 42.35). 08/2009; 460(7254):529-33. DOI: 10.1038/nature08199
Source: PubMed

ABSTRACT MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression, involved in diverse physiological and pathological processes. Although miRNAs can function as both tumour suppressors and oncogenes in tumour development, a widespread downregulation of miRNAs is commonly observed in human cancers and promotes cellular transformation and tumorigenesis. This indicates an inherent significance of small RNAs in tumour suppression. However, the connection between tumour suppressor networks and miRNA biogenesis machineries has not been investigated in depth. Here we show that a central tumour suppressor, p53, enhances the post-transcriptional maturation of several miRNAs with growth-suppressive function, including miR-16-1, miR-143 and miR-145, in response to DNA damage. In HCT116 cells and human diploid fibroblasts, p53 interacts with the Drosha processing complex through the association with DEAD-box RNA helicase p68 (also known as DDX5) and facilitates the processing of primary miRNAs to precursor miRNAs. We also found that transcriptionally inactive p53 mutants interfere with a functional assembly between Drosha complex and p68, leading to attenuation of miRNA processing activity. These findings suggest that transcription-independent modulation of miRNA biogenesis is intrinsically embedded in a tumour suppressive program governed by p53. Our study reveals a previously unrecognized function of p53 in miRNA processing, which may underlie key aspects of cancer biology.

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Available from: Shigeaki Kato, Aug 07, 2014
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    • "cDNA was synthesized from 1 mg of purified RNA by SuperScript III First-Strand cDNA Synthesis System (Invitrogen). Primer sequences for qRT-PCR were described by Suzuki et al. (2009). Primer pairs for each pre-miRNA were designed with the forward primer being within its mature miR-5p and the reverse one being within its mature miR-3p sequences with a maximal extension of 4 nucleotide (nt) except for pre-miR- 21 primers, which extended 7 nt outside of the mature miR-21 sequence. "
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    ABSTRACT: MicroRNAs (miRNAs) regulate the translational potential of their mRNA targets and control many cellular processes. The key step in canonical miRNA biogenesis is the cleavage of the primary transcripts by the nuclear RNase III enzyme Drosha. Emerging evidence suggests that the miRNA biogenic cascade is tightly controlled. However, little is known whether Drosha is regulated. Here, we show that Drosha is targeted by stress. Under stress, p38 MAPK directly phosphorylates Drosha at its N terminus. This reduces its interaction with DiGeorge syndrome critical region gene 8 and promotes its nuclear export and degradation by calpain. This regulatory mechanism mediates stress-induced inhibition of Drosha function. Reduction of Drosha sensitizes cells to stress and increases death. In contrast, increase in Drosha attenuates stress-induced death. These findings reveal a critical regulatory mechanism by which stress engages p38 MAPK pathway to destabilize Drosha and inhibit Drosha-mediated cellular survival. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular Cell 02/2015; 57(4):721-734. DOI:10.1016/j.molcel.2015.01.004 · 14.46 Impact Factor
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    • "miR-16, miR-143, and miR-203 were coordinately suppressed in response to E2 treatment. miR-143, miR-16, miR-145, and miR-203 were post-transcriptionally enhanced by the tumor suppressor , P53 in response to DNA damage [142]. E2/Eα/SP1 is a cell cycle regulatory pathway in breast cancer. "
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    ABSTRACT: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among women worldwide. MicroRNAs (miRNAs) are naturally-occurring, non-coding small RNA molecules that can modulate protein coding-genes, which makes it contributing to nearly all the physiological and pathological processes. Progression of breast cancer and resistance to endocrine therapies has been attributed to the possibility of hormone-responsive miRNAs involved in the regulation of certain signaling pathways. Methodology This review introduces better understanding of miRNAs to provide promising advances for treatment. miRNAs have multiple targets, and they were found to regulate different signaling pathways; consequently it is important to characterize their mechanisms of action and their cellular targets in order to introduce miRNAs as novel and promising therapies. This review summarizes the molecular mechanisms of miRNAs in TGF-Beta signaling, apoptosis, metastasis, cell cycle, ER-signaling, and drug resistance. Finally, miRNAs will be introduced as promising molecules to be used in the fight against breast cancer and its developed drug resistance. Copyright © 2014. Published by Elsevier Inc.
    Clinical Biochemistry 12/2014; 48(6). DOI:10.1016/j.clinbiochem.2014.12.013 · 2.28 Impact Factor
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    • "microRNAs (miRNAs) are noncoding endogenous RNA molecules, 20–25 nucleotides in length, that posttranscriptionally regulate gene expression by specifically targeting the 3 0 untranslated regions (3 0 UTR) of messenger RNAs (mRNAs) (Bartel, 2004, 2009), thus regulating cell differentiation, development, proliferation , and apoptosis (Bueno et al, 2008; Schickel et al, 2008; Urbich et al, 2008; Lynam-Lennon et al, 2009). Some studies have shown that a variety of miRNAs are involved in cancerogenesis and function as oncogenes or tumour suppressors (Suzuki et al, 2009; Cho, 2010; Imam et al, 2010; Wang et al, 2011; Xu et al, 2013). In a recent report, miR-27a was shown to reverse multiple drug resistance in hepatocellular carcinoma cells by inhibiting the FZD7/b-catenin pathway (Chen et al, 2013). "
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    ABSTRACT: Background:The effective mechanisms of microRNAs (miRNAs) functions as oncogenes or tumour suppressors in human hepatocellular carcinoma (HCC) are still obscure. Here, we investigated the function and expression of miR-1228 in HCC.Methods:The role of miR-1228 in HCC was determined by colony formation, transwell, and nude mice xenograft experiments. miR-1228 target gene were identified by EGFP reporter assays, real-time PCR, and western blot analysis. Dual-luciferase reporter assay and real-time PCR analysis are used to examine the regulation of p53.Results:miR-1228 promoted proliferation and metastasis, and facilitated the transition of cell cycle in hepatoma cells. miR-1228 downregulated p53 expression by binding to its 3'UTR. The ectopic expression of p53 abrogated the phenotypes induced by miR-1228. An inverse correlation existed between miR-1228 and p53 expression in hepatoma tissues compared with the adjacent tissues and three hepatoma cell lines. Moreover, we found that p53 suppressed the expression and promoter activity of miR-1228.Conclusions:miR-1228 functions as an oncogene by promoting cell cycle progression and cell mobility and negatively regulates the expression of p53. p53 downregulation in turn leads to an increase in miR-1228 expression, thereby forming a positive feedback loop that contributes to cancerogenesis in HCC.British Journal of Cancer advance online publication, 25 November 2014; doi:10.1038/bjc.2014.593
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