miR24 Inhibits Cell Proliferation by Targeting E2F2, MYC, and Other Cell-Cycle Genes via Binding to “Seedless” 3′UTR MicroRNA Recognition Elements (original) (raw)
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Multiple E2F-Induced MicroRNAs Prevent Replicative Stress in Response to Mitogenic Signaling
Molecular and Cellular Biology, 2010
Transcription of microRNAs (miRNAs) is thought to be regulated similarly to that of protein-coding genes. However, how miRNAs are regulated during the cell division cycle is not well understood. We have analyzed the transcription profiles of miRNAs in response to mitogenic stimulation in primary fibroblasts. About 33% of the miRNAs expressed in these cells are induced upon exit from quiescence. Many of these miRNAs are specifically induced by E2F1 or E2F3 during the G1/S transition and are repressed in E2F1/3-knockout cells. At least four miRNA clusters, let-7a-d, let-7i, mir-15b-16-2, and mir-106b-25, are direct targets of E2F1 and E2F3 during G1/S and are repressed in E2F1/3-null cells. Interestingly, these miRNAs do not contribute to E2F-dependent entry into S phase but rather inhibit the G1/S transition by targeting multiple cell cycle regulators and E2F targets. In fact, E2F1 expression results in a significant increase in S-phase entry and DNA damage in the absence of these mi...
Cell proliferation, 2018
MicroRNAs (miRNAs) as small noncoding RNA molecules function by regulating their target genes negatively. MiR-1258 was widely researched in multicancers, but its role remains unclear in colorectal cancer (CRC). The expression of miR-1258 and its specific target gene were detected in human CRC specimens and cell lines by miRNA RT-PCR, qRT-PCR and Western blot. The effects of miR-1258 on CRC proliferation were evaluated using CCK-8 assays, EdU incorporation, colony formation assays and cell-cycle assays; in vitro and the in vivo effects were investigated using a mouse tumorigenicity model. Luciferase reporter and RIP assays were employed to identify interactions between miR-1258 and its specific target gene. MiR-1258 was downregulated in CRC tissues and CRC cell lines, and upregulated miR-1258 was proved to inhibit proliferation and arrest cell cycle at G0/G1 in vitro and vivo. Luciferase reporter, RIP and western blot assays revealed E2F8 to be a direct target of miR-1258. The effect...
E2F7 regulates transcription and maturation of multiple microRNAs to restrain cell proliferation
Nucleic Acids Research, 2016
E2F transcription factors (E2F1-8) are known to coordinately regulate the expression of a plethora of target genes, including those coding for microRNAs (miRNAs), to control cell cycle progression. Recent work has described the atypical E2F factor E2F7 as a transcriptional repressor of cell cycle-related protein-coding genes. However, the contribution of E2F7 to miRNA gene expression during the cell cycle has not been defined. We have performed a genome-wide RNA sequencing analysis to identify E2F7-regulated miRNAs and show that E2F7 plays as a major role in the negative regulation of a set of miRNAs that promote cellular proliferation. We provide mechanistic evidence for an interplay between E2F7 and the canonical E2F factors E2F1-3 in the regulation of multiple miRNAs. We show that miR-25,-26a,-27b,-92a and-7 expression is controlled at the transcriptional level by the antagonistic activity of E2F7 and E2F1-3. By contrast, let-7 miRNA expression is controlled indirectly through a novel E2F/c-MYC/LIN28B axis, whereby E2F7 and E2F1-3 modulate c-MYC and LIN28B levels to impact let-7 miRNA processing and maturation. Taken together, our data uncover a new regulatory network involving transcriptional and post-transcriptional mechanisms controlled by E2F7 to restrain cell cycle progression through repression of proliferation-promoting miR-NAs.
E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis
E2F1 is a positive regulator of cell cycle progression and also a potent inducer of apoptosis, especially when activated by DNA damage. We identified E2F1-inducible microRNAs (miRNAs) by microarray hybridization and found that the levels of miRNAs 449a and 449b, as well as their host gene CDC20B, are strongly upregulated by E2F1. High miR-449 levels were found in testes, lung, and trachea, but not in testicular and other cancer cells. MiR-449a/b structurally resemble the p53-inducible miRNA 34 family. In agreement with a putative tumor-suppressive role, miR-449a as well as miR-34a reduced proliferation and strongly promoted apoptosis by at least partially p53-independent mechanisms. Both miRNAs reduced the levels of CDK6, implying miR-449 in a negative feedback mechanism for E2F1. Moreover, miR-449a and miR-34a diminished the deacetylase Sirt1 and augmented p53 acetylation. We propose that both miRNAs provide a twofold safety mechanism to avoid excessive E2F1-induced proliferation by cell cycle arrest and by apoptosis. While responding to different transactivators, miRNAs 449 and 34 each repress E2F1, but promote p53 activity, allowing efficient cross-talk between two major DNA damage-responsive gene regulators.
MicroRNAs in cell cycle progression and proliferation: molecular mechanisms and pathways
The microRNAs (miRNAs) are a family of 23 nucleotide non-coding RNAs can regulates protein expression through miRNAs destabilization or translational silencing; circulating miRNAs are potential biomarkers for various diseases, including cancer. In addition, miRNAs also are important therapeutic targets by inhibiting or activating signaling pathways in imbalance and modulate important cellular events such as proliferation, cell cycle and apoptosis. These non-coding RNAs can regulate the expression of cell cycle components such as cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors (CKI) and growth factors. In this review, we provide a comprehensive understanding of the roles of miRNAs in proliferation and cell cycle, considering their key role in physiological and pathological process. In particular, the miRNAs: miR199b-5p, miR-193a-5p, miR-125b-5p, miR-30a-5p and human miR-27b-3p, which are frequently observed in the regulation of proliferative and cell cycle pathways. In this regard, different molecular mechanisms and cellular targets involved in both their ability to limit and amplify proliferation and cell cycle progression have been reported. A single miRNA could target different genes encoding proteins involved in proliferation, cell cycle and apoptosis. Coordinated regulation of a miRNAs may influence a variety of biological cascades. Finally, the critical problems regarding the selectivity of genes and target proteins of these miRNAs from a clinical perspective are discussed. Despite the growing study in this area, further research assesses its role as a biomarker and possible therapy.
An E2F/miR-20a autoregulatory feedback loop
The Journal of biological chemistry, 2007
The E2F family of transcription factors is essential in the regulation of the cell cycle and apoptosis. While the activity of E2F1-3 is tightly controlled by the retinoblastoma family of proteins, the expression of these factors is also regulated at the level of transcription, post-translational modifications and protein stability. Recently, a new level of regulation of E2Fs has been identified, where micro-RNAs (miRNAs) from the mir-17-92 cluster influence the translation of the E2F1 mRNA. We now report that miR-20a, a member of the mir-17-92 cluster, modulates the translation of the E2F2 and E2F3 mRNAs via binding sites in their 3'-untranslated region. We also found that the endogenous E2F1, E2F2, and E2F3 directly bind the promoter of the mir-17-92 cluster activating its transcription, suggesting an autoregulatory feedback loop between E2F factors and miRNAs from the mir-17-92 cluster. Our data also point toward an anti-apoptotic role for miR-20a, since overexpression of thi...
p53-repressed miRNAs are involved with E2F in a feed-forward loop promoting proliferation
Molecular Systems Biology, 2008
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.
MicroRNAs 221 and 222 Bypass Quiescence and Compromise Cell Survival
Cancer Research, 2008
MicroRNAs (miRNA) have tumor suppressive and oncogenic potential in human cancer, but whether and how miRNAs control cell cycle progression is not understood. To address this question, we carried out a comprehensive analysis of miRNA expression during serum stimulation of quiescent human cells. Time course analyses revealed that four miRNAs are up-regulated and >100 miRNAs are down-regulated, as cells progress beyond the G 1 -S phase transition. We analyzed the function of two up-regulated miRNAs (miR-221 and miR-222) that are both predicted to target the cell growth suppressive cyclin-dependent kinase inhibitors p27 and p57. Our results show that miR-221 and miR-222 both directly target the 3 ¶ untranslated regions of p27 and p57 mRNAs to reduce reporter gene expression, as well as diminish p27 and p57 protein levels. Functional studies show that miR-221 and miR-222 prevent quiescence when elevated during growth factor deprivation and induce precocious S-phase entry, thereby triggering cell death. Thus, the physiologic upregulation of miR-221 and miR-222 is tightly linked to a cell cycle checkpoint that ensures cell survival by coordinating competency for initiation of S phase with growth factor signaling pathways that stimulate cell proliferation. [Cancer Res 2008;68(8):2773-80] Requests for reprints:
The E2F1-responsive microRNA-449 promotes apoptosis
2011
E2F1 is a positive regulator of cell cycle progression and also a potent inducer of apoptosis, especially when activated by DNA damage. To identify E2F1-inducible microRNAs, I performed array hybridization and found miR-449a and miR-449b (collectively termed miR-449) to be strongly E2F1-responsive. The levels of miRNAs 449a and 449b, as well as their host gene CDC20B, are strongly upregulated by E2F1 overexpression and DNA damage. Strikingly, miR-449 shares seed sequences and target genes with the miR-34 family, which has tumour suppressive properties. MiR-449 is expressed at high levels and very specifically in testes, lung, and trachea, but not in tumour cells. However, the expression of miR-449 can be reactivated in tumour cells lines by HDAC inhibition, suggesting epigenetic silencing in cancer. Furthermore, miR-449 expression is strongly induced during the mucociliary differentiation of pulmonary epithelia. Exposure to tobacco smoke further increases the levels of miR-449 in ai...