title: E2F1 and RNA binding protein QKI comprise a negative feedback in the cell cycle regulation.
abstract: pRb/E2F1 activity is coordinately regulated during the cell cycle progression, while the molecular strategies safeguarding this pathway are not fully understood. We have previously shown that RNA binding protein QKI inhibits the cell proliferation and promotes the differentiation of gastrointestinal epithelium, suggesting a role of QKI in cell cycle regulation. Here we found that with the cell entry into S phase, QKI expression increased both at the mRNA and protein levels, which was reminiscent of cyclin E expression. Forced expression of E2F1 increased the endogenous level of QKI. Promoter luciferase assay and ChIP analysis identified that the -542~-538 E2F1 binding site was responsible for the upregulation. Increased QKI expression by E2F1, in turn, reduced the E2F1 activity and delayed S-phase entry, forming a negative feedback. As a gene expression regulator, QKI overexpression increased p27, while it decreased cyclin D1 and c-fos expression. Molecularly, p27 and c-fos were direct targets of QKI, while cyclin D1 reduction might be an indirect effect. Taken together, our results reveal that E2F1 directly transcribes QKI, which, in turn, negatively regulates the cell cycle by targeting multiple cell cycle regulators, forming an E2F1-QKI-pRb/E2F1 negative feedback loop.
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Yang
authors.forename: Xiaozhao
authors.initials: X
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Bian
authors.forename: Haiyan
authors.initials: H
authors.lastname: Fu
authors.forename: Mengying
authors.initials: M
authors.lastname: Wei
authors.forename: Jun
authors.initials: J
authors.lastname: Pu
authors.forename: Liang
authors.initials: L
authors.lastname: Jin
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
authors.forename: Zifan
authors.initials: Z
authors.lastname: Lu
mesh_terms: D001665:Binding Sites; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D018809:Proliferating Cell Nuclear Antigen; D016760:Proto-Oncogene Proteins c-fos; C490832:QKI protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C413374:p27 antigen; D019938:Cyclin D1