title: Translational repression of cyclin D3 by a stable G-quadruplex in its 5' UTR: implications for cell cycle regulation.
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.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China.
authors.forename: Heng-You
authors.initials: HY
authors.lastname: Weng
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Huang
authors.forename: Pan-Pan
authors.initials: PP
authors.lastname: Zhao
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Liang-Hu
authors.initials: LH
authors.lastname: Qu
mesh_terms: D020121:5' Untranslated Regions; D001483:Base Sequence; D002453:Cell Cycle; D049109:Cell Proliferation; D056743:Cyclin D3 / Q000235:genetics*; D054856:G-Quadruplexes; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000737:chemistry; D006163:Ribonuclease T1 / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; C534696:CCND3 protein, human; D056743:Cyclin D3; D012333:RNA, Messenger; D006163:Ribonuclease T1