miR-661 downregulates both Mdm2 and Mdm4 to activate p53

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.

Time, Dose and Ataxia Telangiectasia Mutated (ATM) Status Dependency of Coding and Noncoding RNA Expression after Ionizing Radiation Exposure

“…Indeed, transcription is much more complex than simply the production of transcripts of protein-coding genes and a number of miRNAs have been identified which target DDR components, e.g., miR-100, miR-101 and miR-421 down-regulate ATM expression (58-60), miR-125b and miR-504 directly regulate TP53 expression (61, 62) and miR-605 and miR-661 target the MDM2 gene (63,64).…”

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

“…Immunoblot analysis was performed as previously described (60). The list of antibodies used is provided in SI Materials and Methods.…”

MicroRNA‐661 modulates redox and metabolic homeostasis in colon cancer

“…The final output of the effect of this miR relies not only on the specific cancer cell type, but also on multiple players associated to the cell biology: oncogenes, tumor suppressors, metabolites and/or oxidative stress associated molecules. In this sense, depending on p53 status, miR661 may suppress (p53‐wild‐type) or promote (p53‐mutated) cancer aggressiveness by a direct effect on mdm2 and mdm4 (Hoffman et al ., 2014). In a model of Snail1‐induced EMT in breast cancer cells, Vetter and collaborators identified miR661 as a key Snail1‐induced miR required for efficient invasion (Vetter et al ., 2010).…”