Vimentin, a novel regulator of the transcription factor ATF4 and osteoblast differentiation

Abstract

This project is concerned with mechanisms underlying osteoblast differentiation, a critical process during bone remodeling and repair. In this dissertation I explored novel regulators for osteoblast differentiation by identifying functional partners of ATF4, an osteoblast-enriched transcription factor important for osteoblast differentiation and bone formation. Through a combination of biochemical, molecular and cellular experiments, I identified and confirmed vimentin, an intermediate filament protein, as a novel inhibitor for ATF4's transcriptional activity and osteoblast differentiation. Furthermore, through series of genetic and pharmacological interventions in vitro and in vivo, I revealed that the vimentin serves as a downstream mediator that responds TGF beta signaling by binding and inhibiting ATF4 in immure osteoblasts via a non-canonical pathway. Therefore, this research uncovers a novel mechanism by which a cytoskeletal protein, vimentin, acts as a brake on differentiation in immature osteoblasts by its interaction with ATF4.