FIAT, the factor‐inhibiting ATF4‐mediated transcription, also represses the transcriptional activity of the bZIP factor FRA‐1

Abstract

FIAT is a leucine zipper protein whose name was coined for its interaction with ATF4 and subsequent blockage of ATF4-directed osteocalcin gene transcription. FIAT lacks a basic DNA-binding domain but contains three leucine zippers; it heterodimerizes with ATF4 to prohibit binding to DNA. FIAT could also potentially interact with additional basic domain-leucine zipper transcriptional regulators of osteoblast activity, such as FRA-1. We have found that FIAT inhibits transcriptional activation by a FRA-1/c-JUN heterodimer without affecting transcription mediated by a c-JUN homodimer. The repressor effect of FIAT on FRA-1-dependent transcription was measured using reporter constructs for the natural FRA-1 targets, Mmp-9 and Mgp. The FIAT-FRA-1 interaction is mediated through the second leucine zipper of FIAT. These data confirm an additional target of the FIAT transcriptional repressor activity and suggest that FIAT can both modulate early osteoblast activity by interacting with ATF4 and regulate later osteoblast function through inhibition of FRA-1.