1] Department of Cancer Biology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, Pennsylvania 19107, USA [2] Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, Pennsylvania 19107, USA [3] Research Center for Translational Medicine, Key Laboratory for Basic Research in Cardiology, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
Nat Commun. 2013;4:2812. doi: 10.1038/ncomms3812.
Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates the pRB protein and promotes G1/S cell-cycle progression and oncogenesis. Dicer is a central regulator of miRNA maturation, encoding an enzyme that cleaves double-stranded RNA or stem-loop-stem RNA into 20-25 nucleotide long small RNA, governing sequence-specific gene silencing and heterochromatin methylation. The mechanism by which the cell cycle directly controls the non-coding genome is poorly understood. Here we show that cyclin D1(-/-) cells are defective in pre-miRNA processing which is restored by cyclin D1a rescue. Cyclin D1 induces Dicer expression in vitro and in vivo. Dicer is transcriptionally targeted by cyclin D1, via a cdk-independent mechanism. Cyclin D1 and Dicer expression significantly correlates in luminal A and basal-like subtypes of human breast cancer. Cyclin D1 and Dicer maintain heterochromatic histone modification (Tri-m-H3K9). Cyclin D1-mediated cellular proliferation and migration is Dicer-dependent. We conclude that cyclin D1 induction of Dicer coordinates microRNA biogenesis.
周期蛋白 D1 编码全酶的调节亚基，该全酶可使 pRB 蛋白磷酸化，并促进 G1/S 细胞周期进程和肿瘤发生。Dicer 是 miRNA 成熟的核心调节剂，编码一种能够将双链 RNA 或茎环茎 RNA 切割成 20-25 个核苷酸长的小 RNA 的酶，调控序列特异性基因沉默和异染色质甲基化。细胞周期直接控制非编码基因组的机制尚不清楚。本文中我们发现，周期蛋白 D1(-/-)细胞在前 miRNA 加工中存在缺陷，而通过 cyclin D1a 挽救可恢复该过程。体外和体内实验均表明，cyclin D1 可诱导 Dicer 的表达。cyclin D1 通过一种不依赖 CDK 的机制，在转录水平上靶向 Dicer。cyclin D1 和 Dicer 的表达在人乳腺癌的腔 A 型和基底样亚型中显著相关。cyclin D1 和 Dicer 维持异染色质组蛋白修饰（Tri-m-H3K9）。cyclin D1 介导的细胞增殖和迁移依赖于 Dicer。综上，我们的结论是，cyclin D1 诱导 Dicer 协调了 miRNA 的生物发生。
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