miRNA regulation during oncogene-induced senescence
Aberrant oncogene activation induces cellular senescence, an irreversible growth arrest which acts as a barrier against tumor formation. To identify miRNAs involved in oncogene-induced senescence we arrayed miRNA expression in primary human fibroblasts (Tig3) following over-expression of B-RAF. 18 miRNA were significantly regulated (P<0.001) 4 days after B-RAF activation; in particular, miR-34a expression increased ∼8-fold. In addition, miR-34a is up-regulated in mouse fibroblasts undergoing replicative senescence. In agreement with previous reports, we find that miR-34a reduces cellular proliferation and induces cell cycle arrest. Using microarrays, we have identified a number of putative miR-34a targets involved in oncogene-induced senescence and we are now evaluating their ability to mediate the cellular effects of miR-34a. Although members of the miR-34 family are known p53 target genes, our data indicate that miR-34a is regulated independently of p53 during oncogene-induced senescence. Hence, miR-34a responds to several independent cancer-related pathways thereby underlining the importance of miR-34a as an important tumor suppressor. We are currently investigating the regulation of miR-34a in normal and senescent cells using ChIP and promoter reporter assays.
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