Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development
ABSTRACT In multiple myeloma (MM), an incurable B cell neoplasm, mutation or deletion of p53 is rarely detected at diagnosis. Using small-molecule inhibitors of MDM2, we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. The results suggest that these miRNAs are positive regulators of p53 and that their downregulation plays a key role in MM development.
- SourceAvailable from: Atanu Ghorai
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- "Various miRNAs are produced as per requirement of the cell but the regulation or detail mechanism(s) of biogenesis of miRNAs are yet to be elucidated . miRNA genes can have transcription start site (TSS) like the coding genes and transcription factors that are used for transcription of mRNA are also used for miRNA transcription (Aguda et al., 2008; Pichiorri et al., 2010; Wang et al., 2010a,b). Again, miRNA could also be produced in cell as a byproduct of post-transcriptional processing of coding genes using splicing machinery and lariat de-branching enzymes bypassing the conventional nuclear miRNA biogenesis pathway by Drosha cleavage as mentioned above (Okamura et al., 2007; Flynt et al., 2010). "
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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- "Transgenic mice overexpressing SerpinB33 in the liver have been shown to over-express mTOR (Villano et al., 2013) and therefore the deregulation of miR-100 promoted by SerpinB3 could enhance the " cell survival effect " induced by mTOR in hepatic cancer cells. – miR-215 is considered to be transcriptionally activated but also a positive regulator of p53 (Pichiorri et al., 2010). This miRNA, found down-regulated in HCC (Su et al., 2009), has demonstrated tumor suppressive properties in multiple myeloma, metastatic renal carcinoma and renal childhood neoplasms (Senanayake et al., 2012a). "
ABSTRACT: miRNAs are small non-coding RNAs which target complementary mRNAs sequences, usually resulting in gene silencing. They can exhibit oncogenic or tumor suppressor properties, modulating cell homeostasis. Several data have documented that miRNAs are typically deregulated in different types of cancers, including hepatocellular carcinoma (HCC). Some of the miRNAs, such as miR-122, miR-221, miR-1 and miR-21 have been found to repress post-transcriptionally the expression of genes involved in cell cycle regulation, cell proliferation, apoptosis, cell migration and invasion. In HCC serum levels of miR-122, miR-221 and miR-16 have been described deregulated, suggesting that they may be used as molecular targets for early detection, prognosis and treatment. The ov-serpin SerpinB3 was found previously increased in liver tumor cancers and associated with apoptosis resistance, increased cell proliferation and invasiveness. Recent data indicate that this serpin may enhance its oncogenic potential through inhibition of several tumor suppressive miRNAs, typically described in HCC.Life sciences 02/2014; 100(1). DOI:10.1016/j.lfs.2014.01.073 · 2.30 Impact Factor
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- "). Moreover, p53 has been shown to induce miRs, including miR-215 (Pichiorri and others 2010). Additionally, p53-responsive miRs, including miR-215, have been shown to regulate the cell cycle (Braun and others 2008; Georges and others 2008). "
ABSTRACT: Cystic fibrosis (CF) is due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which cause a massively proinflammatory phenotype in the CF airway. The chemical basis of the inflammation is hyperproduction of interleukin-8 (IL-8) by CF airway epithelial cells, based on both an intrinsic mutation-dependent mechanism and by infection. In infection-free, cultured CF lung epithelial cells, high levels of the microRNA (miR), miR-155, is responsible for hyperexpression of IL-8. However, whether infection-induced IL-8 expression in CF cells is also mediated by miR-155 is not known. We have hypothesized that miR-155 might be a general mediator of enhanced IL-8 expression in CF cells, either in response to other cytokine/chemokine mediators of inflammation, or after exposure to infectious agents. Here we find that a reduction in miR-155 accompanies suppression of IL-8 by either the anti-inflammatory cytokine IL-10 or by inhibition of ambient IL-1β with a neutralizing antibody. However, attempts to elevate IL-8 levels with either intact bacteria [viz. a mucoid strain of Pseudomonas aeruginosa (PA)], or lipopolysaccharide were unable to elevate miR-155 above its intrinsically high level in the absence of these agents. Instead, in response to PA infection, the CF cells modestly suppress the expression of miR-155, and express a novel set of miRs, including miR-215. We find that ex vivo CF lung epithelial cells also express high levels of both miR-155 and miR-215. The predicted module of infection-induced mRNA targets focuses on activation of the NFκB-signaling pathway, and on the proapoptotic p53-signaling pathway. We interpret these data to suggest that that CF lung epithelial cells respond to PA or bacterial cell products with a novel miR program that may carry with it serious challenges to survival.Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 01/2013; DOI:10.1089/jir.2012.0074 · 3.90 Impact Factor