Nuclear localization of folate receptor alpha: a new role as a transcription factor

Folic acid (FA) has traditionally been associated with prevention of neural tube defects; more recent work suggests that it may also be involved in in the prevention of adult onset diseases. As the role of FA in human health and disease expands, it also becomes more critical to understand the mechanisms behind FA action. In this work we examined the hypothesis that folate receptor alpha (FR alpha) acts as a transcription factor. FR alpha is a GPI-anchored protein and a component of the caveolae fraction. The work described here shows that FR alpha translocates to the nucleus, where it binds to cis-regulatory elements at promoter regions of Fgfr4 and Hes1, and regulates their expression. The FR alpha recognition domain mapped to AT rich regions on the promoters. Until this time FR alpha has only been considered as a folate transporter, these studies describe a novel role for FRa as a transcription factor.