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 cyclinE expression. Forced expression of E2F1 increased the endogenous level of QKI. Promoter luciferase assay and ChIP analysis identified the -542∼-538 E2F1 binding site was responsible for the upregulation. Increased QKI expression by E2F1 in turn reduced the E2F1 activity and delayed the S-phase entry, forming a negative feedback. As a gene expression regulator, QKI overexpression increased p27 while decreased cyclinD1 and c-fos expression. Molecularly, p27 and c-fos were direct targets of QKI while cyclinD1 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. © 2011 Landes Bioscience.