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

Abstract

microRNAs (miR) are small noncoding RNA molecules that have recently emerged as critical regulators of gene expression and are often deregulated in cancer. In particular, miRs encoded by the miR-15a, miR-16-1 cluster seem to act as tumor suppressors. Here, we evidence that the miR-15a, miR-16-1 cluster and related miR-15b, miR-16-2 cluster comprise miRs regulated by E2F1, a pivotal transcription factor that can induce both proliferation and cell death. E2F1 is a critical downstream target of the tumor suppressor retinoblastoma (RB). The RB pathway is often inactivated in human tumors resulting in deregulated E2F activity. We show that expression levels of the 4 mature miRs, miR-15a, miR-16-1 and miR-15b, miR-16-2, as well as their precursor primiRNAs, are elevated upon activation of ectopic E2F1. Moreover, activation of endogenous E2Fs upregulates expression of these miRs and endogenous E2F1 binds their respective promoters. Importantly, we corroborate that miR-15a/b inhibits expression of cyclin E, the latter a key direct transcriptional target of E2F pivotal for the G 1 /S transition, raising the possibility that E2F1, miR-15, and cyclin E constitute a feed-forward loop that modulates E2F activity and cell-cycle progression. In support of this, ectopic expression of miR-15 inhibits the G 1 /S transition, and, conversely, inhibition of miR-15 expression enhances E2F1-induced upregulation of cyclin E1 levels. Furthermore, inhibition of both miR-15 and miR-16 enhances E2F1-induced G 1 /S transition. In summary, our data identify the miR-15 and miR-16 families as novel transcriptional targets of E2F, which, in turn, modulates E2F activity. Mol Cancer Res; 9(4); 440-7. Ó2011 AACR.

Functional high-throughput screening identifies the miR-15 microRNA family as cellular restriction factors for Salmonella infection

“…Previously, it has been reported that members of the miR-15 family are under the direct transcriptional control of E2F1 (ref. 24), a transcription factor best known for its regulation of the gene expression programme required for cell cycle progression. E2F1 binds to the promoters of DLEU2 and SMC4 genes leading to increased expression of the miRNAs that are processed from these genes.…”

MicroRNAs: Biogenesis, Roles for Carcinogenesis and as Potential Biomarkers for Cancer Diagnosis and Prognosis

“…Similarly, up regulation of mir-17-92 and miR-21 by targeting PTEN (phosphatase and tensin homolog protein act as a tumour suppressor gene in the regulation of the cell cycle) and inhibit expression of the transcription factor E2F1, whereby miR-221/222 up regulation are targeting p27Kip1 (a cell-cycle regulatory protein that interacts with cyclin-CDK2/-CDK4) and inhibiting cell cycle progression at G1, promote cellular proliferation and are capable of up regulating the components of the apoptotic signalling pathway and transforming to cancer cells resistant or susceptible to extrinsic factors at the same checkpoint (Petrocca et al, 2008). Conversely, oncogenic miRNA; miR-15a, miR-16-1 cluster and related miR-15b, miR-16-2 cluster in CLL patients regulated by E2F1 (a critical downstream target of the pRB) often inactivated in human tumours resulting in dysregulation of E2F activity which have been reported that reduces the levels of cyclin D1, cyclin D3, cyclin E1, and CDK6 was triggers an accumulation of multiple cell cycle-promoting genes and was predicted that both miRNAs contribute to apoptosis by decreasing the levels of the apoptotic inhibitor Bcl-2 at G1/S phase (Ofir et al, 2011). Recent findings determine that knockdown of microRNA-34a decreased the rate of apoptosis caused by PRIMA-1 which is a small molecule that restores tumour suppressor function to mutant p53 to induced apoptosis in the cell cycle (Duan et al, 2010).…”

Regulation of miR106b cluster through the RB pathway

“…Noncoding RNA encompass a variety of discrete entities, including micro RNA (miRNA), ultra conserved long non-coding RNA and pyknons. While several miRNA species are regulated via E2F and RB, the mechanisms coordinating such altered expression of miRNA, [11][12][13][14] the targets and overall mode of regulation has remained obscure relative to coding genes.…”

“…[14][15][16] For example, deregulated miRNA expression has been implicated in aberrant proliferation, genome stability and epithelial-mesenchymal transition. [17][18][19] Analyses of miRNA expression in breast cancer tumor specimens have demonstrated association with specific breast cancer subtypes.…”