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: 23.52). 10/2010; 18(4):367-81. DOI: 10.1016/j.ccr.2010.09.005
Source: PubMed


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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Available from: sung-suk Suh, Aug 30, 2015
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    • "On the flip side, p53 inhibits MDM2 expression using several miRNAs and establishes the regulatory circuit between p53 and MDM2 (Figure 2). For instance, miR-192/194/215, miR-143/145, and miR-605, which are the transcriptional targets of p53, directly inhibit MDM2 expression [68, 114, 115]. miR-29 family members are also p53-inducible miRNAs and indirectly control the MDM2 level by targeting p85α, a regulatory subunit of PI3 kinase (PI3K), in the PI3K/AKT/MDM2 axis [116, 117]. "
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    • "MDM2 may be over-expressed in some cases of multiple myeloma [23], [24] through mechanisms such as gene amplification or chromosomal trisomy [24]. In addition, epigenetic suppression of the promoter for the micro RNA 194-2-192 cluster may also enhance MDM2 expression [25]. This over-expression has been shown to result in enhanced cell cycle progression, proliferation, and survival of myeloma cells, in part through down-regulation of the cyclin-dependent kinase inhibitor p21 [26]. "
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    • "MDM2 is an oncogene that was firstly discovered in a locus amplified on double minute chromosomes in a tumorigenic mouse cell line (3T3-DM) [25]. The main function of MDM2 is to inhibit p53 bioactivity by blocking the transcriptional activity of p53 and promoting p53 protein degradation [26]–[28]. "
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