p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC.
Aberrant oncogene activation induces cellular senescence, an irreversible growth arrest that acts as a barrier against tumorigenesis. To identify microRNAs (miRNAs) involved in oncogene-induced senescence, we examined the expression of miRNAs in primary human TIG3 fibroblasts after constitutive activation of B-RAF. Among the regulated miRNAs, both miR-34a and miR-146a were strongly induced during senescence. Although members of the miR-34 family are known to be transcriptionally regulated by p53, we find that miR-34a is regulated independently of p53 during oncogene-induced senescence. Instead, upregulation of miR-34a is mediated by the ETS family transcription factor, ELK1. During senescence, miR-34a targets the important proto-oncogene MYC and our data suggest that miR-34a thereby coordinately controls a set of cell cycle regulators. Hence, in addition to its integration in the p53 pathway, we show that alternative cancer-related pathways regulate miR-34a, emphasising its significance as a tumour suppressor.
Christoffersen
N R
NR
Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
Shalgi
R
R
Frankel
L B
LB
Leucci
E
E
Lees
M
M
Klausen
M
M
Pilpel
Y
Y
Nielsen
F C
FC
Oren
M
M
Lund
A H
AH
D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002461:Cell Line, Transformed; D016922:Cellular Senescence / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D009857:Oncogenes / Q000502:physiology; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism
C494112:ELK1 protein, human; C000715470:MAS1 protein, human; C542542:MIRN146 microRNA, human; C522425:MIRN34 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D050807:ets-Domain Protein Elk-1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf