microRNA-496 - A new, potentially aging-relevant regulator of mTOR.
Recent findings strongly support a role for small regulatory RNAs in the regulation of human lifespan yet little information exists about the precise underlying mechanisms. Although extensive studies on model organisms have indicated that reduced activity of the nutrient response pathway, for example as a result of dietary restriction, can extend lifespan through the suppression of the protein kinase mechanistic target of rapamycin (mTOR), it still is subject of debate whether this mechanism is operative in humans as well. Here, we present findings indicating that human microRNA (miR)-496 targets 2 sites within the human mTOR 3'UTR. Coexpression of miR-496 with different fusion transcripts, consisting of the luciferase transcript and either wild-type mTOR 3'UTR or mTOR 3'UTR transcript with the miR-496 binding sites singly or combined mutated, confirmed this prediction and revealed cooperativity between the 2 binding sites. miR-496 reduced the mTOR protein level in HeLa-K cells, and the levels of miR-496 and mTOR protein were inversely correlated in Peripheral Blood Mononuclear Cells (PBMC), with old individuals (n = 40) harbouring high levels of miR-496 relative to young individuals (n = 40). Together, these findings point to the possibility that miR-496 is involved in the regulation of human aging through the control of mTOR.
a Department of General-, Visceral-, Vascular- and Pediatric Surgery , University of Saarland Medical Center , Homburg/Saar , Germany.
Claudia
C
Rubie
a Department of General-, Visceral-, Vascular- and Pediatric Surgery , University of Saarland Medical Center , Homburg/Saar , Germany.
Kathrin
K
Kölsch
a Department of General-, Visceral-, Vascular- and Pediatric Surgery , University of Saarland Medical Center , Homburg/Saar , Germany.
Beata
B
Halajda
b Institute of Clinical Haemostaseology and Transfusion Medicine, University of Saarland Medical Center , Homburg/Saar , Germany.
Hermann
H
Eichler
c Institute of Medical Biometrics, Epidemiology, and Medical Informatics (IMBEI), University of Saarland Medical Center , Homburg/Saar , Germany.
Stefan
S
Wagenpfeil
d Jose Carreras Research Center, University of Saarland Medical Center , Homburg/Saar , Germany.
Klaus
K
Roemer
a Department of General-, Visceral-, Vascular- and Pediatric Surgery , University of Saarland Medical Center , Homburg/Saar , Germany.
Matthias
M
Glanemann
D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D001483:Base Sequence; D001782:Blood Donors; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006367:HeLa Cells; D064368:Healthy Volunteers; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D020413:3' Untranslated Regions; C000590213:MIRN496 microRNA, human; D035683:MicroRNAs; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D008156:Luciferases; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
Human aging; PBMC; gene regulation; mTOR; microRNA