Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development

Department of Molecular Virology, Comprehensive Cancer Center, Ohio State University, Columbus, 43210, USA.
Cancer cell (Impact Factor: 23.89). 10/2010; 18(4):367-81. DOI: 10.1016/j.ccr.2010.09.005
Source: PubMed

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.

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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). "
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    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). "
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    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). "
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