Bifunctional small molecules that induce nuclear localization and targeted transcriptional regulation.

ABSTRACT: The aberrant localization of proteins in cells is a key factor in the development of various diseases, including cancer and neurodegenerative disease. To better understand and potentially manipulate protein localization for therapeutic purposes, we engineered bifunctional compounds that bind to proteins in separate cellular compartments. We show these compounds induce nuclear import of cytosolic cargoes, using nuclear-localized BRD4 as a "carrier" for co-import and nuclear trapping of cytosolic proteins. We use this system to calculate kinetic constants for passive diffusion across the nuclear pore and demonstrate single-cell heterogeneity in response to these bifunctional molecules, with cells requiring high carrier to cargo expression for complete import. We also observe incorporation of

SUBMITTER: Gibson WJ 

PROVIDER: S-EPMC10350064 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature