Format

Send to

Choose Destination
Cell Death Differ. 2014 Feb;21(2):302-9. doi: 10.1038/cdd.2013.146. Epub 2013 Oct 18.

miR-661 downregulates both Mdm2 and Mdm4 to activate p53.

Author information

1
1] Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel [2] Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
2
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
3
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

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.

PMID:
24141721
PMCID:
PMC3890952
DOI:
10.1038/cdd.2013.146
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center