MYC Protein Inhibits Transcription of the MicroRNA Cluster MC-let-7a-1 similar to let-7d via Noncanonical E-box
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摘要The human microRNA cluster MC-let-7a-1 similar to let-7d, with three members let-7a-1, let-7f-1, and let-7d, is an important cluster of the let-7 family. These microRNAs play critical roles in regulating development and carcinogenesis. Therefore, precise control of MC-let-7a-1 similar to let-7d level is critical for cellular functions. In this study, we first showed that the expression of these three members was significantly reduced in human hepatocellular carcinoma HepG2 cells as compared with the immortalized human liver L02 cells. We demonstrated that the MC-let-7a-1 similar to let-7d cluster was encoded by a single polycistronic transcript driven by a 10-kb upstream promoter, with two MYC-binding sites. Importantly, MYC inhibited MC-let-7a-1 similar to let-7d promoter activity via binding to the noncanonical E-box 3 downstream of the transcription start sites, whereas it enhanced promoter activity by binding to the canonical E-box 2 upstream of the transcription start sites. We found that although the binding affinity of MYC to E-box 2 was stronger than E-box 3, the binding quantum of MYC to E-box 3 was significantly higher in cancerous HepG2 cells as compared with the noncancerous L02 cells. In addition, forced expression of let-7 could reverse the MYC-mediated cell proliferation. These findings suggested that in L02 cells with a low level of MYC, MYC binds mainly to E-box 2 to enhance MC-let-7a-1 similar to let-7d expression. However, in HepG2 cells with an elevated MYC, the extra MYC could bind to E-box 3 to suppress the transcription of MC-let-7a-1 similar to let-7d and thus enable HepG2 cells to maintain a high level of MYC and a low level of let-7 microRNAs simultaneously.
著者Wang ZF, Lin S, Li JLJ, Xu ZH, Yao H, Zhu X, Xie D, Shen Z, Sze J, Li K, Lu G, Chan DTM, Poon WS, Kung HF, Lin MCM
期刊名稱Journal of Biological Chemistry
出版年份2011
月份11
日期18
卷號286
期次46
出版社American Society for Biochemistry and Molecular Biology
頁次39703 - 39714
國際標準期刊號0021-9258
電子國際標準期刊號1083-351X
語言英式英語
Web of Science 學科類別Biochemistry & Molecular Biology; BIOCHEMISTRY & MOLECULAR BIOLOGY

上次更新時間 2020-24-11 於 00:20