E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis

Abstract

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.

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).…”

Association between microRNA single nucleotide polymorphisms and the risk of hepatocellular carcinoma

“…It has been verified that miR-449 is down-regulated or lost in gastric cells, lung adenocarcinoma cell and testicular cancer cells [17][18][19][20] . In addition, our research demonstrates for the first time that in miRNA449b (rs10061133), G allele is significantly associated with an increased risk of susceptibility to HCC compared with A allele.…”

“…Some researches revealed that miR-3152 and miR-449 are involved in cancer [17][18][19][20] . MiR-3152 is up regulated in PDAC (pancreatic ductal adenocarcinoma), and miR-449 is down-regulated or lost in gastric cells, lung adenocarcinoma cells and testicular cancer cells.…”

E2F7 regulates transcription and maturation of multiple microRNAs to restrain cell proliferation

“…Significant progress in the understanding of E2F-mediated regulation of gene expression has been achieved by the finding that many microRNA-coding genes are bona fide E2F target genes (13)(14)(15)(16)(17)(18)(19)(20). In line with the complex nature of the E2F pathway, many reports have uncovered an essential role for E2F-regulated microRNAs in modulating distinct cellular processes, most notably pathways involved in neoplastic transformation (21,22).…”