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RNA Biol. 2012 Aug;9(8):1099-109. doi: 10.4161/rna.21210. Epub 2012 Aug 1.

Translational repression of cyclin D3 by a stable G-quadruplex in its 5' UTR: implications for cell cycle regulation.

Author information

1
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China.

Abstract

cyclin D3 (CCND3) is one of the three D-type cyclins that regulate the G1/S phase transition of the cell cycle. Expression of CCND3 is observed in nearly all proliferating cells; however, the presence of high levels of CCND3 has been linked to a poor prognosis for several types of cancer. Therefore, further mechanistic studies on the regulation of CCND3 expression are urgently needed to provide therapeutic implications. In this study, we report that a conserved RNA G-quadruplex-forming sequence (hereafter CRQ), located in the 5' UTR of mammalian CCND3 mRNA, is able to fold into an extremely stable, intramolecular, parallel G-quadruplex in vitro. The CRQ G-quadruplex dramatically reduces the activity of a reporter gene in human cell lines, but it has little impact on its mRNA level, indicating a translational repression. Moreover, the CRQ sequence in its natural context inhibits translation of CCND3. Disruption of the G-quadruplex structure by G/U-mutation or deletion results in an elevated expression of CCND3 and an increased phosphorylation of Rb, a downstream target of CCND3, which promotes progression of cells through the G1 phase. Our results add to the growing understanding of the regulation of CCND3 expression and provide a potential therapeutic target for cancer treatment.

PMID:
22858673
PMCID:
PMC3551864
DOI:
10.4161/rna.21210
[Indexed for MEDLINE]
Free PMC Article

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