Abstract
The p53 pathway is pivotal in tumor suppression. Cellular p53 activity is subject to tight regulation, in which the two related proteins Mdm2 and Mdm4 have major roles. The delicate interplay between the levels of Mdm2, Mdm4 and p53 is crucial for maintaining proper cellular homeostasis. microRNAs (miRNAs) are short non-coding RNAs that downregulate the level and translatability of specific target mRNAs. We report that miR-661, a primate-specific miRNA, can target both Mdm2 and Mdm4 mRNA in a cell type-dependent manner. miR-661 interacts with Mdm2 and Mdm4 RNA within living cells. The inhibitory effect of miR-661 is more prevalent on Mdm2 than on Mdm4. Interestingly, the predicted miR-661 targets in both mRNAs reside mainly within Alu elements, suggesting a primate-specific mechanism for regulatory diversification during evolution. Downregulation of Mdm2 and Mdm4 by miR-661 augments p53 activity and inhibits cell cycle progression in p53-proficient cells. Correspondingly, low miR-661 expression correlates with bad outcome in breast cancers that typically express wild-type p53. In contrast, the miR-661 locus tends to be amplified in tumors harboring p53 mutations, and miR-661 promotes migration of cells derived from such tumors. Thus, miR-661 may either suppress or promote cancer aggressiveness, depending on p53 status.
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Abbreviations
- miRNA:
-
microRNA
- WTp53:
-
wild-type p53
- DBD:
-
DNA-binding domain
- ER+:
-
estrogen receptor positive
- GOF:
-
gain of function
- FBS:
-
fetal bovine serum
- miR-661:
-
miR-661 mimic
- miR-C:
-
miR-control mimic
- si-miR-661:
-
miR-661 inhibitor
- si-miR-C:
-
miR-control inhibitor
- sip53:
-
p53 siRNA
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Acknowledgements
We thank Judy Lieberman for generous help with pull-down expertise, Debora Marks for bioinformatics ideas and Gilad Fuchs for the fruitful discussions. This work was supported in part by an FP7 grant 201102 (ONCOMIRS) from the European Research Council (to MO and YP), the ‘Ideas’ program of the European Research Council (to YP), grant R37 CA40099 from the National Cancer Institute (to MO), the Dr. Miriam and Sheldon G Adelson Medical Research Foundation (to MO), the Ben May Charitable Trust (to YP) and the Weizmann Institute Kahn Center (to MO and YP). MO is an incumbent of the Andre Lwoff Chair in Molecular Biology. YP is an incumbent of the Ben-May Professorial Chair.
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Hoffman, Y., Bublik, D., Pilpel, Y. et al. miR-661 downregulates both Mdm2 and Mdm4 to activate p53. Cell Death Differ 21, 302–309 (2014). https://doi.org/10.1038/cdd.2013.146
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DOI: https://doi.org/10.1038/cdd.2013.146
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