Nucleic Acids Research Advance Access originally published online on January 19, 2009
Nucleic Acids Research 2009 37(5):1672-1681; doi:10.1093/nar/gkp002
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Nucleic Acids Research, 2009, Vol. 37, No. 5 1672-1681
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer
1Department of Biological Sciences, Seoul National University, 2Cancer Research Institute, Seoul National University College of Medicine and 3Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
*To whom correspondence should be addressed. Tel: +82 2 880 9120; Fax: +82 2 887 0244; Email: narrykim{at}snu.ac.kr Correspondence may also be addressed to Han-Kwang Yang. Tel: +82 2 2072 3797; Fax: +82 2 3672 0047; Email: hkyang{at}snu.ac.kr
Received August 5, 2008. Revised December 31, 2008. Accepted January 1, 2009.
microRNAs (miRNAs) play integral roles in diverse processes including tumorigenesis. miRNA gene loci are often found in close conjunction, and such clustered miRNA genes are transcribed from a common promoter to generate polycistronic primary transcript. The primary transcript (pri-miRNA) is then processed by two RNase III proteins to release the mature miRNAs. Although it has been speculated that the miRNAs in the same cluster may play related biological functions, this has not been experimentally addressed. Here we report that the miRNAs in two clusters (miR-106b
93 25 and miR-222 221) suppress the Cip/Kip family members of Cdk inhibitors (p57Kip2, p21Cip1 and p27Kip1). We show that miR-25 targets p57 through the 3'-UTR. Furthermore, miR-106b and miR-93 control p21 while miR-222 and miR-221 regulate both p27 and p57. Ectopic expression of these miRNAs results in activation of Cdk2 and facilitation of G1/S phase transition. Consistent with these results, both clusters are abnormally upregulated in gastric cancer tissues compared to the corresponding normal tissues. Ectopic expression of miR-222 cluster enhanced tumor growth in the mouse xenograft model. Our study demonstrates the functional associations between clustered miRNAs and further implicates that effective cancer treatment may require a combinatorial approach to target multiple oncogenic miRNA clusters.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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