Kumamoto K, Spillare EA, Fujita K, Horikawa I, Yamashita T, Appella E et al.. Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence. Cancer Res 68: 3193-3203

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4258, USA.
Cancer Research (Impact Factor: 9.33). 06/2008; 68(9):3193-203. DOI: 10.1158/0008-5472.CAN-07-2780
Source: PubMed


Nutlin-3, an MDM2 inhibitor, activates p53, resulting in several types of cancer cells undergoing apoptosis. Although p53 is mutated or deleted in approximately 50% of all cancers, p53 is still functionally active in the other 50%. Consequently, nutlin-3 and similar drugs could be candidates for neoadjuvant therapy in cancers with a functional p53. Cellular senescence is also a phenotype induced by p53 activation and plays a critical role in protecting against tumor development. In this report, we found that nutlin-3a can induce senescence in normal human fibroblasts. Nutlin-3a activated and repressed a large number of p53-dependent genes, including those encoding microRNAs. mir-34a, mir-34b, and mir-34c, which have recently been shown to be downstream effectors of p53-mediated senescence, were up-regulated, and inhibitor of growth 2 (ING2) expression was suppressed by nutlin-3a treatment. Two candidates for a p53-DNA binding consensus sequence were found in the ING2 promoter regulatory region; thus, we performed chromatin immunoprecipitation and electrophoretic mobility shift assays and confirmed p53 binding directly to those sites. In addition, the luciferase activity of a construct containing the ING2 regulatory region was repressed after p53 activation. Antisense knockdown of ING2 induces p53-independent senescence, whereas overexpression of ING2 induces p53-dependent senescence. Taken together, we conclude that nutlin-3a induces senescence through p53 activation in normal human fibroblasts, and p53-mediated mir34a, mir34b, and mir34c up-regulation and ING2 down-regulation may be involved in the senescence pathway.

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Available from: Makoto Nagashima, Sep 30, 2015
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    • "Up-regulation of miR-34a, miR-34b and miR-34c in NHF-hTEFT cells (normal human fibroblast cells) by Nutlin-3 (an MDM2 inhibitor) induce senescence pathways in a p53 dependent manner [112]. "
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    Current Cancer Drug Targets 10/2014; 14(8). DOI:10.2174/1568009614666141020100337 · 3.52 Impact Factor
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    • "These miRNAs are termed as " Mirtrons " (Berezikov et al., 2007; Chan and Slack, 2007; Ruby et al., 2007; Westholm and Lai, 2011; Havens et al., 2012).Therefore, it is not very clear whether biogenesis of miRNA is a separate , parallel process as that of coding gene expression or linked with it. Numerous studies to date have established the role of miR- NAs in diverse cellular processes like stem cell differentiation, heart development (Chen et al., 2006; Zhao et al., 2007; Ivey et al., 2008), insulin secretion (Plaisance et al., 2006), apoptosis (Lukiw and Pogue, 2007; Tarasov et al., 2007), aging (Kumamoto et al., 2008; Maes et al., 2008), immunity (Chen et al., 2004; Rodriguez et al., 2007), cell proliferation, metabolism (Hwang and Mendell, 2007; Taganov et al., 2007; Stefani and Slack, 2008) etc. Recent studies also revealed that certain miRNAs are strongly associated with various diseases such as diabetes (Ciccacci et al., 2013; van de Bunt et al., 2013), cancer (Calin and Croce, 2006; Blenkiron and Miska, 2007; Wuchty et al., 2012; Benetatos et al., 2013), cardiovascular disease (Zhao et al., 2005; Sayed et al., 2007; Zhao et al., 2007), neurodegenerative diseases (Hébert et al., 2008; Wang et al., 2008a,b) and hence miRNAs can be treated as potential biomarker or diagnostic tool (Keller et al., 2011; Fassina et al., 2012; Jones et al., 2012; Weiland et al., 2012; Cuk et al., 2013; Endo et al., 2013). "
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    ABSTRACT: MicroRNAs target specific mRNA(s) to silence its expression and thereby regulate various cellular processes. We have investigated miRNA gene counts in chromosomes for 20 different species and observed wide variation. Certain chromosomes have extremely high number of miRNA gene compared with others in all the species. For example, high number of miRNA gene in X chromosome and the least or absence of miRNA gene in Y chromosome was observed in all species. To search the criteria governing such variation of miRNA gene counts in chromosomes, we have selected three parameters- length, number of non-coding and coding genes in a chromosome. We have calculated Pearson's correlation coefficient of miRNA gene counts with length, number of non-coding and coding genes in a chromosome for all 20 species. Major number of species showed that number of miRNA gene was not correlated with chromosome length. Eighty five percent of species under study showed strong positive correlation coefficient (r ≥ 0.5) between the numbers of miRNA gene vs. non-coding gene in chromosomes as expected because miRNA is a sub-set of non-coding genes. 55% species under study showed strong positive correlation coefficient (r ≥ 0.5) between numbers of miRNA gene vs. coding gene. We hypothesize biogenesis of miRNA largely depends on coding genes, an evolutionary conserved process. Chromosomes having higher number of miRNA genes will be most likely playing regulatory roles in several cellular processes including different disorders. In humans, cancer and cardiovascular disease associated miRNAs are mostly intergenic and located in Chromosome 19, X, 14, and 1.
    Frontiers in Genetics 04/2014; 5:100. DOI:10.3389/fgene.2014.00100
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    • "miR-34c is now reported to have several functions against different biological processes. miR-34c was first reported to be a target of p53 by Corney35, and several reports also showed that miR-34c is induced by p53, and mediates apoptosis, cellular senescence and the cell cycle404142. Recent reports indicated that down-regulation of miR-34c is associated with cancer growth and metastasis, and miR-34c acts as a tumor-suppressor4344454647. "
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