MicroRNA-449 in cell fate determination

The microRNAs 449a, b and c (miR-449) are potent inducers of cell death, cell cycle arrest, and/or cell differentiation. They belong to the same family as the p53-responsive microRNAs miR-34. Instead of p53, however, the cell cycle regulatory transcription factor E2F1 induces miR-449. All members of this microRNA family are capable of mediating cell cycle arrest and apoptosis and might thereby contribute to tumor suppression. Underlying mechanisms include the downregulation of histone acetyl transferases and consecutive activation of p53, but also the targeting of cyclin dependent kinases and their association partners. Thus, miR-34 and miR-449 provide an asymmetric feedback loop to balance E2F and p53 activities. More recently, it was discovered that miR-449 displays strong tissue specificity, with high levels in lung and testes. Two model systems (Xenopus embryos and cultured human cells) revealed that miR-449 is essential for the development of ciliated epithelia, and this appears to depend on miR-449-mediated modulation of the Notch signaling pathway. Here we summarize our current knowledge on cell fate determination by miR-449, and we propose future directions to explore the function of miR-449 in cell regulation and organismal development. MiR-449 helps to ensure proper cell function but also to avoid cancer, marking a close link between cell differentiation and tumor suppression.