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

TY - JOUR

T1 - p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC

AU - Christoffersen, N R

AU - Shalgi, R

AU - Frankel, L B

AU - Leucci, E

AU - Lees, M

AU - Klausen, M

AU - Pilpel, Y

AU - Nielsen, F C

AU - Oren, M

AU - Lund, Anders H.

PY - 2010/2

Y1 - 2010/2

N2 - 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.

AB - 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.

KW - Cell Aging

KW - Cell Cycle

KW - Cell Division

KW - Cell Line, Transformed

KW - Fibroblasts

KW - Humans

KW - MicroRNAs

KW - Neoplasms

KW - Oncogenes

KW - Proto-Oncogene Proteins B-raf

KW - Proto-Oncogene Proteins c-myc

KW - Tumor Suppressor Protein p53

KW - Up-Regulation

KW - ets-Domain Protein Elk-1

U2 - 10.1038/cdd.2009.109

DO - 10.1038/cdd.2009.109

M3 - Journal article

C2 - 19696787

SN - 1350-9047

VL - 17

SP - 236

EP - 245

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

IS - 2

ER -