Foxo3a regulates apoptosis by negatively targeting miR-21.
MicroRNAs are a class of small non-coding RNAs and participate in the regulation of apoptotic program. Although miR-21 is able to inhibit apoptosis, its expression regulation and downstream targets remain to be fully elucidated. Here we report that the transcriptional factor Foxo3a initiates apoptosis by transcriptionally repressing miR-21 expression. Our results showed that doxorubicin could simultaneously induce the translocation of Foxo3a to the cell nuclei and a reduction in miR-21 expression. Knockdown of Foxo3a resulted in an elevation in miR-21 levels, whereas enforced expression of Foxo3a led to a decrease in miR-21 expression. In exploring the molecular mechanism by which Foxo3a regulates miR-21, we observed that Foxo3a bound to the promoter region of miR-21 and suppressed its promoter activity. These results indicate that Foxo3a can transcriptionally repress miR-21 expression. In searching for the downstream targets of miR-21 in apoptosis, we found that miR-21 suppressed the translation of Fas ligand (FasL), a pro-apoptotic factor. Furthermore, Foxo3a was able to up-regulate FasL expression through down-regulating miR-21. Our data suggest that Foxo3a negatively regulates miR-21 in initiating apoptosis.
Wang
Kun
K
Cancer Research Group, National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Li
Pei-Feng
PF
D020413:3' Untranslated Regions; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D004317:Doxorubicin / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D021381:Protein Transport; D015398:Signal Transduction; D013347:Subcellular Fractions
D020413:3' Untranslated Regions; D000903:Antibiotics, Antineoplastic; C499517:FOXO3 protein, human; D053222:Fas Ligand Protein; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D004317:Doxorubicin