MicroRNA‐29b Functions as a Repressor of Intestinal Mucosal Growth by Targeting Cyclin‐dependent Kinase 2

Abstract

Integrity of the intestinal epithelium is tightly regulated by numerous factors including microRNAs. We recently found that mucosal growth inhibition associates with an increase in microRNA‐29b (miR‐29b), but its exact role in epithelial homeostasis remains unknown. This study determined if miR‐29b inhibits intestinal mucosal growth by repressing cyclin‐dependent kinase (CDK) 2.MethodsStudies were conducted in mice and IEC‐6 cells, and miR‐29b function was examined by its ectopic overexpression and silencing.ResultsmiRNA‐29b silencing by the systemic delivery of LNA‐antimiR‐29b not only increased CDK2 but also stimulated small intestinal mucosal growth in mice. In contrast, increased levels of miRNA‐29b in IEC‐6 cells repressed CDK2 expression and caused growth arrest in G1 phase. miR‐29b repressed CDK4 translation through direct interaction with the CDK2 mRNA, and point mutation of miR‐29b binding‐site on the 3′‐untranslated region of the CDK2 mRNA prevented miR‐29b‐induced repression of CDK2 translation. CDK2 gene transcription was also inhibited by miRNA‐29b through a process involving p53. miR‐29b increased p53, whereas deletion of p53 binding‐site in the CDK2‐promoter blocked miRNA‐29b‐induced repression of CDK2 transcription.ConclusionsThese results indicate that miRNA‐29b inhibits intestinal mucosal growth by repressing CDK2 expression through distinct mechanisms. NIH Grant DK‐57819