Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2

Nucleic Acids Res. 2016 Apr 7;44(6):2846-58. doi: 10.1093/nar/gkw027. Epub 2016 Feb 9.


Most RNAs generated by the human genome have no protein-coding ability and are termed non-coding RNAs. Among these include circular RNAs, which include exonic circular RNAs (circRNA), mainly found in the cytoplasm, and intronic RNAs (ciRNA), predominantly detected in the nucleus. The biological functions of circular RNAs remain largely unknown, although ciRNAs have been reported to promote gene transcription, while circRNAs may function as microRNA sponges. We demonstrate that the circular RNA circ-Foxo3 was highly expressed in non-cancer cells and were associated with cell cycle progression. Silencing endogenous circ-Foxo3 promoted cell proliferation. Ectopic expression of circ-Foxo3 repressed cell cycle progression by binding to the cell cycle proteins cyclin-dependent kinase 2 (also known as cell division protein kinase 2 or CDK2) and cyclin-dependent kinase inhibitor 1 (or p21), resulting in the formation of a ternary complex. Normally, CDK2 interacts with cyclin A and cyclin E to facilitate cell cycle entry, while p21works to inhibit these interactions and arrest cell cycle progression. The formation of this circ-Foxo3-p21-CDK2 ternary complex arrested the function of CDK2 and blocked cell cycle progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Cycle / genetics
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cyclin A / genetics
  • Cyclin A / metabolism*
  • Cyclin E / genetics
  • Cyclin E / metabolism*
  • Cyclin-Dependent Kinase 2 / genetics
  • Cyclin-Dependent Kinase 2 / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Cytoplasm / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / chemistry
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Nucleic Acid Conformation
  • Organ Specificity
  • Protein Binding
  • RNA, Untranslated / chemistry
  • RNA, Untranslated / genetics
  • RNA, Untranslated / metabolism*
  • Signal Transduction


  • Cyclin A
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p21
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • RNA, Untranslated
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2