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: 41.46). 08/2009; 460(7254):529-33. DOI: 10.1038/nature08199
Source: PubMed


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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    • "The p53 stress response protein is a transcription factor with a crucial role in tumour suppression (Lowe et al. 2004; Vousden and Lane 2007). It regulates various biological activities (Menendez et al. 2007, 2009; Vousden and Prives 2009) including, apoptosis (Bensaad et al. 2006; Vousden 2006), cell cycle (Kastan et al. 1992; Kuerbitz et al. 1992), senescence (Garbe et al. 2007), immune response (Taura et al. 2008), cell differentiation (Molchadsky et al. 2008), motility (Qin et al. 2009) and migration (Roger et al. 2006; Singh et al. 2007), angiogenesis (Pal et al. 2001; Teodoro et al. 2006; Zhang et al. 2000), DNA (Helton and Chen 2007) and energy (Green and Chipuk 2006; Matoba et al. 2006; Vousden and Ryan 2009) metabolism, microRNA processing (Suzuki et al. 2009), cell–cell communication (Yu et al. 2006) and the DNA damage response and repair (de Souza-Pinto et al. 2004; Sengupta and Harris 2005; Sommers et al. 2005). Normal levels of p53 protein are low, due to rapid ubiquitin-dependent proteasomal degradation which is controlled largely by the E3 ubiquitin ligase MDM2 (Brooks and Gu 2006) (known as HDM2 in human), which in turn is also a target of transcriptional regulation by p53 (Murray-Zmijewski et al. 2008). "
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    ABSTRACT: A small library of anticancer, cell-permeating, stapled peptides based on potent dual-specific antagonist of p53–MDM2/MDMX interactions, PMI-N8A, was synthesized, characterized and screened for anticancer activity against human colorectal cancer cell line, HCT-116. Employed synthetic modifications included: S-alkylation-based stapling, point mutations increasing hydrophobicity in key residues as well as improvement of cell-permeability by introduction of polycationic sequence(s) that were woven into the sequence of parental peptide. Selected analogue, ArB14Co, was also tested in vivo and exhibited potent anticancer bioactivity at the low dose (3.0 mg/kg). Collectively, our findings suggest that application of stapling in combination with rational design of polycationic short analogues may be a suitable approach in the development of physiologically active p53–MDM2/MDMX peptide inhibitors.
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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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    Molecular Cell 02/2015; 57(4):721-734. DOI:10.1016/j.molcel.2015.01.004 · 14.02 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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