miR-22 forms a regulatory loop in PTEN/AKT pathway and modulates signaling kinetics.
BACKGROUND
The tumor suppressor PTEN (phosphatase and tensin homolog) is a lipid phosphatase that converts PIP3 into PIP2 and downregulates the kinase AKT and its proliferative and anti-apoptotic activities. The FoxO transcription factors are PTEN downstream effectors whose activity is negatively regulated by AKT-mediated phosphorylation. PTEN activity is frequently lost in many types of cancer, leading to increased cell survival and cell cycle progression.


RESULTS
Here we characterize the widely expressed miR-22 and report that miR-22 is a novel regulatory molecule in the PTEN/AKT pathway. miR-22 downregulates PTEN levels acting directly through a specific site on PTEN 3'UTR. Interestingly, miR-22 itself is upregulated by AKT, suggesting that miR-22 forms a feed-forward circuit in this pathway. Time-resolved live imaging of AKT-dependent FoxO1 phosphorylation revealed that miR-22 accelerated AKT activity upon growth factor stimulation, and attenuated its down regulation by serum withdrawal.


CONCLUSIONS
Our results suggest that miR-22 acts to fine-tune the dynamics of PTEN/AKT/FoxO1 pathway.
Bar
Nadav
N
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Dikstein
Rivka
R
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D015398:Signal Transduction; D016385:TATA Box / Q000235:genetics; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt; D012319:RNA Polymerase II; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human