Article

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

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
    • "Recent studies showed that the miR-125b [79], miRNA-380-5p, miR-34, and miR-200 families inhibit the expression of p53 and its related family member p63 in cancer cells [80]. miRNAs expressed in preimplantation embryos, such as miR-16-1, miR-143, and miR-145, were up-regulated by p53-and p68/p72-dependent pathways upon DNA damage in human colon cancer cell lines [81]. Additionally, p53 transcriptionally regulates the miR-192, miR-194, miR-215, and miR-17-92 clusters, and the miR-34 family that targets genes involved in G1/S and G2/M checkpoints8283848586. "
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    ABSTRACT: Active DNA repair pathways are crucial for preserving genomic integrity and are likely among the complex mechanisms involved in the normal development of preimplantation embryos. MicroRNAs (miRNA), short non-coding RNAs, are key regulators of gene expression through the post-transcriptional and post-translational modification of mRNA. The association of miRNA expression with infertility or polycystic ovarian syndrome has been widely investigated; however, there are limited data regarding the importance of miRNA regulation in DNA repair during preimplantation embryo development. In this article, we review normal miRNA biogenesis and consequences of aberrant miRNA expression in the regulation of DNA repair in gametes and preimplantation embryos.
    No preview · Article · Feb 2016 · Journal of Reproduction and Development
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    • "First, there was no increase in the expression of the bi-cistronic pri-miRNA encoding miR- 143-3p and miR-145-5p, despite the sustained expression of the processed miRNAs (Fig 4A). Thus, increased miR-143-3P and miR-145-5p is most consistent with the previously reported post-transcriptional mechanism [24, 46]. This was deduced from the fact that for a small increase in pri-miRNA (1.3 fold) to yield very large increases in the mature product (50 to 70 "
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    ABSTRACT: The p53 tumour suppressor is a transcription factor that can regulate the expression of numerous genes including many encoding proteins and microRNAs (miRNAs). The predominant outcomes of a typical p53 response are the initiation of apoptotic cascades and the activation of cell cycle checkpoints. HT29-tsp53 cells express a temperature sensitive variant of p53 and in the absence of exogenous DNA damage, these cells preferentially undergo G1 phase cell cycle arrest at the permissive temperature that correlates with increased expression of the cyclin-dependent kinase inhibitor p21WAF1. Recent evidence also suggests that a variety of miRNAs can induce G1 arrest by inhibiting the expression of proteins like CDK4 and CDK6. Here we used oligonucleotide microarrays to identify p53-regulated miRNAs that are induced in these cells undergoing G1 arrest. At the permissive temperature, the expression of several miRNAs was increased through a combination of either transcriptional or post-transcriptional regulation. In particular, miR-34a-5p, miR-143-3p and miR-145-5p were strongly induced and they reached levels comparable to that of reference miRNAs (miR-191 and miR-103). Importantly, miR-34a-5p and miR-145-5p are known to silence the Cdk4 and/or Cdk6 G1 cyclin-dependent kinases (cdks). Surprisingly, there was no p53-dependent decrease in the expression of either of these G1 cdks. To search for other potential targets of p53-regulated miRNAs, p53-downregulated mRNAs were identified through parallel microarray analysis of mRNA expression. Once again, there was no clear effect of p53 on the repression of mRNAs under these conditions despite a remarkable increase in p53-induced mRNA expression. Therefore, despite a strong p53 transcriptional response, there was no clear evidence that p53-responsive miRNA contributed to gene silencing. Taken together, the changes in cell cycle distribution in this cell line at the permissive temperature is likely attributable to transcriptional upregulation of the CDKN1A mRNA and p21WAF1 protein and not to the down regulation of CDK4 or CDK6 by p53-regulated miRNAs.
    Full-text · Article · Feb 2016 · PLoS ONE
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    • "Interestingly, miR-143 and miR-145 clustered on chromosome 5q33.1 and both displayed decreased expression profiles in many cancer types. TP53 loss-offunction led to a decreased level of both miR-143 and miR-145 through attenuating the maturation processing [69]. In addition, RAS activation led to down-regulation of the miR-143/145 cluster through RREB1 (RAS-responsive element-binding protein) activation that represses the miR- 143/145 cluster promoter [70]. "
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    ABSTRACT: The highly conserved RAS-mitogen activated protein kinase (MAPK) signaling pathway is involved in a wide range of cellular processes including differentiation, proliferation, and survival. Somatic mutations in genes encoding RAS-MAPK components frequently occur in many tumors, making the RAS-MAPK a critical pathway in human cancer. Since the pioneering study reporting that let-7 miRNA acted as tumor suppressor by repressing the RAS oncogene, growing evidence has suggested the importance of miRNAs targeting the RAS-MAPK in oncogenesis. MiRNAs alterations in human cancers may act as a rheostat of the oncogenic RAS signal that is often amplified as cancers progress. However, specific mechanisms leading to miRNAs deregulation and their functional consequences in cancer are far from being fully elucidated. In this review, we provide an experimental-validated map of RAS-MAPK oncomiRs and tumor suppressor miRNAs from transmembrane receptor to downstream ERK proteins. MiRNAs could be further considered as potential genetic biomarkers for diagnosis, prognosis, or therapeutic purpose.
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