Functional variants at the miRNA binding sites of the E2F1 gene and its mRNA expression

Abstract

Abstract. The transcription factor E2F1 is a key regulator of cell proliferation and apoptosis, and deregulated expression of E2F1 has been frequently found in a number of malignancies. Previous studies have indentified that E2F1 genetic 3' untranslated region (3'UTR) microRNA (miRNA) binding site variants are significantly associated with cancer risk; however, the roles of genetic variants in the E2F1 3'UTR in its post-transcriptional regulation have not been elucidated. Hence, using mRNA expression data from the HapMap online database, we analyzed the association between the variants at the miRNA binding sites of E2F1 and its mRNA expression. In the present study, we report the identification of 5 variants of putative miRNA binding sites in the E2F1 3'UTR by bioinformatic analysis. Among them, rs3213180 was found to be significantly associated with E2F1 expression in lymphoblastoid cell lines from the HapMap database (P=0.045); however, no significant association was demonstrated in this study for rs3213182 (P=0.345) and rs3213183 (P=0.402). This study demonstrated that rs3213180 may be a putative variant mediating the post-transcriptional regulation of the E2F1 target gene. In conclusion, 3'UTR polymorphism is significantly associated with E2F1 expression in lymphoblastoid cell lines. However, this finding requires validation in further functional analysis of the underlying mechanism involving E2F1 transcriptional activity associated with variants in the 3'UTR. IntroductionThe E2F family plays a crucial role in the control of the cell cycle and action of tumor suppressor proteins (1). E2F1 belongs to the E2F family of transcription factors, coordinating the expression of key genes involved in cell cycle regulation and progression (2). The E2F1 gene is located on chromosome 20 q, spanning approximately 10.71 kb, and it contains 7 exons (3). Due to its pivotal and multifunctional role in cell cycle control, E2F1 is expected to be a significant player in carcinogenesis (4). Excess of E2F1 may promote proliferation, but at the same time it may also enhance apoptosis, and there are examples where overexpression or lack of E2F1 has both positive and negative effects on tumorigenesis (5). The delicate balance between growth and death appears to depend on the level of E2F1 deregulation, but also on the cell context background (2).It is well known that genetic variants in microRNA (miRNA) binding regions can result in altered gene functions. miRNAs are capable of regulating the E2F activity, and miRNA dysregulation has been implicated in malignancy. For instance, E2F1 directly binds to the promoter of the miR-17~92 cluster, activating its transcription, which in turn negatively modulates translation of E2F1 mRNAs by binding sites in their 3'UTR (6,7). In addition, certain studies have shown that E2F1 and E2F2 variants may play important roles in carcinogenesis (8,9). Considering that E2F1 is crucial for E2F family-dependent apoptosis (10), and the role of variants in miRNA binding sites of E2F1 remains unknown, in the...

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