Translational repression of cyclin D3 by a stable G-quadruplex in its 5' UTR.

cyclin D3 (CC ND3) is one of the three D-type cyclins that regulate the G1/S phase transition of the cell cycle. Expression of CC ND3 is observed in nearly all proliferating cells; however, the presence of high levels of CC ND3 has been linked to a poor prognosis for several types of cancer. Therefore, further mechanistic studies on the regulation of CC ND3 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 CC ND3 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 CC ND3. Disruption of the G-quadruplex structure by G/U-mutation or deletion results in an elevated expression of CC ND3 and an increased phosphorylation of Rb, a downstream target of CC ND3, which promotes progression of cells through the G1 phase. Our results add to the growing understanding of the regulation of CC ND3 expression and provide a potential therapeutic target for cancer treatment. [ABSTRACT FROM AUTHOR]