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

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9437445 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5403 (Electronic) Linking ISSN: 13509047 NLM ISO Abbreviation: Cell Death Differ Subsets: MEDLINE

Publication: <2003->: London : Nature Publishing Group
Original Publication: London : Edward Arnold, c1994-

Cellular Senescence/*genetics ; Fibroblasts/*cytology ; Fibroblasts/*physiology ; MicroRNAs/*genetics ; Proto-Oncogene Proteins c-myc/*genetics; Cell Cycle/genetics ; Cell Division/genetics ; Cell Line, Transformed ; Humans ; MicroRNAs/metabolism ; Neoplasms/genetics ; Neoplasms/pathology ; Oncogenes/physiology ; Proto-Oncogene Mas ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation/physiology ; ets-Domain Protein Elk-1/genetics ; ets-Domain Protein Elk-1/metabolism

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.

0 (ELK1 protein, human)
0 (MAS1 protein, human)
0 (MIRN146 microRNA, human)
0 (MIRN34 microRNA, human)
0 (MYC protein, human)
0 (MicroRNAs)
0 (Proto-Oncogene Mas)
0 (Proto-Oncogene Proteins c-myc)
0 (TP53 protein, human)
0 (Tumor Suppressor Protein p53)
0 (ets-Domain Protein Elk-1)
EC 2.7.11.1 (BRAF protein, human)
EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)

Date Created: 20090822 Date Completed: 20100713 Latest Revision: 20211203

20240829

10.1038/cdd.2009.109

19696787