Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs

摘要: MicroRNAs regulate networks of genes to orchestrate cellular functions. MiR-125b, the vertebrate homologue Caenorhabditis elegans microRNA lin-4, has been implicated in regulation neural and hematopoietic stem cell homeostasis, analogous how lin-4 regulates cells C. elegans. Depending on context, miR-125b proposed both apoptosis proliferation. Because p53 network is a central regulator proliferation, dual roles raise question what might be regulated by miR-125b. By using gain- loss-of-function screen for targets humans, mice, zebrafish validating these with luciferase assay novel miRNA pull-down assay, we demonstrate that directly represses 20 network. These include regulators like Bak1, Igfbp3, Itch, Puma, Prkra, Tp53inp1, Tp53, Zac1, also cell-cycle cyclin C, Cdc25c, Cdkn2c, Edn1, Ppp1ca, Sel1l, We found that, although each miRNA–target pair was seldom conserved, pathway conserved at level. Our results lead us propose buffers fine-tunes activity regulating dose proliferative apoptotic regulators, implications tissue homeostasis oncogenesis.