p53‐repressed miRNAs are involved with E2F in a feed‐forward loop promoting proliferation

Abstract

Normal cell growth is governed by a complicated biological system, featuring multiple levels of control, often deregulated in cancers. The role of microRNAs (miRNAs) in the control of gene expression is now increasingly appreciated, yet their involvement in controlling cell proliferation is still not well understood. Here we investigated the mammalian cell proliferation control network consisting of transcriptional regulators, E2F and p53, their targets and a family of 15 miRNAs. Indicative of their significance, expression of these miRNAs is downregulated in senescent cells and in breast cancers harboring wild-type p53. These miRNAs are repressed by p53 in an E2F1-mediated manner. Furthermore, we show that these miRNAs silence antiproliferative genes, which themselves are E2F1 targets. Thus, miRNAs and transcriptional regulators appear to cooperate in the framework of a multi-gene transcriptional and post-transcriptional feed-forward loop. Finally, we show that, similarly to p53 inactivation, overexpression of representative miRNAs promotes proliferation and delays senescence, manifesting the detrimental phenotypic consequence of perturbations in this circuit. Taken together, these findings position miRNAs as novel key players in the mammalian cellular proliferation network.

miR-15 and miR-16 Are Direct Transcriptional Targets of E2F1 that Limit E2F-Induced Proliferation by Targeting Cyclin E

“…Recently, a number of E2F-regulated miRNAs have been identified, including the miR-17-92, miR-106a-363, and miR-106b-25 clusters as well as miR-449a and miR-449b (18)(19)(20)(21)(22)(23)(24). In line with the complex nature of the RB/E2F pathway, some of these E2F-regulated miRNAs regulate E2Fs and/or other pathway components, thereby inhibiting E2F activity (18)(19)(20)22).…”

FOXP3 and FOXP3-regulated microRNAs suppress SATB1 in breast cancer cells

“…The mechanisms and consequences of miR deregulation within a cancer cell are still being determined, although it is likely that changes in the levels and the activity of transcriptional regulators and the miR-processing machinery, coupled with alterations in miR copy number, contribute to the overall deregulation of miR expression (Zhang et al, 2006;Selcuklu et al, 2009). There is now evidence for the participation of miR and transcription factor combinations in feedback and feed-forward loops (Tsang et al, 2007;Brosh et al, 2008;Bartel, 2009;Re et al, 2009), and such miR/transcription factor feed-forward loops enhance the robustness and responsiveness of the gene regulation network (Filipowicz et al, 2008).…”

Hypoxic Pulmonary Vascular Smooth Muscle Cell Proliferation

“…Decreased expression of p21 and increased expression of HIF-1α via suppression of p53 protein may mitigate hypoxic pulmonary arterial remodeling and PASMC proliferation. Recently, several groups identified microRNAs (miRNAs) regulated by p53 [33,34]. miRNAs are non-coding RNA molecules which modulate gene expression by binding to complementary sequences in the coding -or the 3`-untranslated region of target mRNAs.…”