Chemical Genetics of 14-3-3 Regulation and Role in Tumor Development

摘要

The 14-3-3 proteins are a family of adaptor proteins that bind to more than 200 protein partners and affect their biological function by altering their stability, catalytic activity and subcellular localization. While the structure or 14-3-3 is well studied and the biology of the 14-3-3 interaction with their partners is understood, the regulation of these proteins remains debatable. Specifically, the mode of export of 14-3-3 proteins from the nucleus is not clear. A number of studies suggest a role for the CRM1 nuclear export receptor while other reports provide different findings. Here we describe a number of small molecules that affect the export of 14-3-3 sigma. One molecule, TK10, was previously shown to affect the transport of the transcription factor FKHR in a ORMI-independent manner. A second molecule, Haloprogin, an approved anti4ungal drug of unknown mechanism, was identified in a high-throughput screen of small molecules inhibitors of 14-3-3 export. Using the Rev-GFP reporter for nuclear export, we find that Haloprogin does not interfere with the CRM1 pathway. Haloprogin activity on different 14-3-3 isoforms is also studied. Therefore we determine that 14-3-3 sigma export from the nucleus is ORMI-independent. The results also suggest a mode of action for the drug Haloprogin.