MICRORNA AND RNA BINDING PROTEINS: THE POSTTRANSCRIPTIONAL REGULATORS OF FOXO EXPRESSION

Abstract

FOXO (Forkhead box O) transcription factors, member of the forkhead family of proteins, a family which is characterized by the presence of ‘forkhead box’ a conserved DNA binding domain. Multiple environmental and other factors control FOXO activity by altering the various mechanisms of post-translational, transcriptional and post-transcriptional modifications. Regulation of FOXO expression at the posttranscriptional level came out as a new area of interest in controlling FOXO functions in normal and in cancerous cells. At posttranscriptional level, FOXO expression is regulated by microRNA and RNA binding proteins (HuR and QKI). MicroRNAs directly target multiple regions of the 3’-UTR of FOXO mRNA to down regulate its expression. Various miRNAs have been found to regulate expression of FOXO in different physiological and pathological conditions, including cancer. HuR overexpression in MDA-MB-231, breast cancer cell line results in stabilized FOXO1 mRNA and enhanced level of the FOXO1 factor. HuR-mediated up-regulation of FOXO1 causes apoptosis in cancer cells, upon exposure to a stressful stimulus. QKI has been found to reduce the stability of FOXO1 mRNA as well as to alter expression of FOXO1 in breast cancer cells. Collecting evidence suggests that this post-transcriptional level of regulation of FOXO expression is involved in reactions and adaptations to various stressful conditions. Alteration in FOXO posttranscriptional regulation is often linked to different disease conditions. Future research has to be done to resolve the complexities of posttranscriptional regulatory interactions that will create new knowledge about the novel pathways of disease processes and development of corresponding novel therapeutic molecule.