miR-16 family induces cell cycle arrest by regulating multiple cell cycle genes

Abstract

MicroRNAs (miRNAs) are a class of small regulatory RNAs that are thought to be involved in diverse biological processes by regulating gene expression. Numerous miRNAs have been identified in various species, and many more miRNAs remain to be detected. Generally, hundreds of mRNAs have been predicted to be potential targets of one miRNA, so it is a great challenge to identify the genuine miRNA targets. Here, we generated the cell lines depleted of Drosha protein and screened dozens of transcripts (including Cyclin D1) regulated potentially by miRNA-mediated RNA silencing pathway. On the basis of miRNA expressing library, we established a miRNA targets reverse screening method by using luciferase reporter assay. By this method, we found that the expression of Cyclin D1 (CCND1) was regulated by miR-16 family directly, and miR-16 induced G1 arrest in A549 cells partially by CCND1. Furthermore, several other cell cycle genes were revealed to be regulated by miR-16 family, including Cyclin D3 (CCND3), Cyclin E1 (CCNE1) and CDK6. Taken together, our data suggests that miR-16 family triggers an accumulation of cells in G0/G1 by silencing multiple cell cycle genes simultaneously, rather than the individual target.

MiR-15a and miR-16 induce autophagy and enhance chemosensitivity of Camptothecin

“…26 As tumor suppressors, miR-15a and miR-16 were shown to inhibit cancer cell proliferation by targeting various cyclins and CDKs and induce apoptosis through down-regulating the anti-apoptotic gene Bcl-2. [27][28][29] In the present study, we report miR-15a and miR-16 directly target Rictor, an important component in mTORC2 pathway. Overexpression of miR-15a/16 or knockdown Rictor downregulate mTORC1/p70S6K, increase autophagic activity.…”

microRNA Portraits in Human Vulvar Carcinoma

“…Among our HPV-positive samples, the expression of these two microRNAs was downregulated, which may be an important factor for the high proliferative status of the HPV-positive tumors. Finally, miR-16, found upregulated among HPV-negative samples, was showed as having antitumor action through inhibition of CCND1, CCND2, CCND3, bcl-2, and other genes (41)(42)(43). When targeting CCND1 and CCND2, miR-16 seems to induce G 1 -phase arrest (38).…”

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

“…One example is cyclin D1, which is regulated by miR449a [35] , miR-193b [36] , miR-15/16 [37][38][39] , miR-19a [40] , miR-195 [41] , and miR-302a [42] . The cyclin D1 binding proteins CDK4 and CDK6 are also regulated by a number of miRNAs, including miR-107 [43] , miR-449a [44] , miR-129 [45] , miR-125b [46] , miR-15/16 [39] , miR-24 [47] , miR-195 [41] , and miR-124a [48] . Another important G 1 /S regulator cyclin E, is down-regulated by miR-16 [37] and miR-195 [49] .…”