Abstract
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.
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Abbreviations
- 4-OHT:
-
4-hydroxytamoxifen
- 4-tU:
-
4-thiouridine
- 5-FU:
-
5-fluorouracil
- ChIP:
-
chromatin immunoprecipitation
- EtOH:
-
ethanol
- miRNA:
-
microRNA
- PI:
-
propidium iodide
- SA-β-gal:
-
senescence-associated beta-galactosidase
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Acknowledgements
We thank Dr. Robert A Hipskind for kindly providing us with the ELK1 expression construct and Dr. Martin Bushell for kindly providing us with the MYC 3′UTR luciferase constructs, pLSV-M3′ and pLSV-M3′MUT. Work in the authors’ laboratories has been supported by the EC FP7 funding (ONCOMIRS, grant agreement number 201102. The commission is not liable for any use that may be made of the information herein), the Vilhelm Pedersen and Hustrus Foundation, the Danish National Research Foundation, the Danish Medical Research Council, the Danish Cancer Society and the Association for International Cancer Research. This publication reflects only the authors’ views.
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Christoffersen, N., Shalgi, R., Frankel, L. et al. p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death Differ 17, 236–245 (2010). https://doi.org/10.1038/cdd.2009.109
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DOI: https://doi.org/10.1038/cdd.2009.109
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