p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC

• Published in: Cell death and differentiation Vol. 17; no. 2; pp. 236 - 245
• Main Authors: Christoffersen, N R, Shalgi, R, Frankel, L B, Leucci, E, Lees, M, Klausen, M, Pilpel, Y, Nielsen, F C, Oren, M, Lund, A H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2010; Nature Publishing Group
• Subjects: Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell cycle; Cell Cycle - genetics; Cell Cycle Analysis; Cell death; Cell Division - genetics; Cell Line, Transformed; Cellular Senescence - genetics; DNA damage; ets-Domain Protein Elk-1 - genetics; ets-Domain Protein Elk-1 - metabolism; Fibroblasts - cytology; Fibroblasts - physiology; Genes; Humans; Kinases; Life Sciences; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Morphology; Neoplasms - genetics; Neoplasms - pathology; Oncogenes - physiology; original-paper; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Senescence; Stem Cells; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors; Up-Regulation - physiology; Denmark; Israel; senescence; miRNA; B-RAF; miR-34a; MYC
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2009.109

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.