Arsenic trioxide is a potent inhibitor of the interaction of SMRT corepressor with its transcription factor partners, including the PML-retinoic acidreceptor alpha oncoprotein found in human acute promyelocytic leukemia

The SMRT corepressor complex participates in transcriptional repression by a diverse array of vertebrate transcription factors. The ability to recruit SMRT appears to play a crucial role in leukemogenesis by the PML-retinoic acid receptor alpha (RAR alpha) oncoprotein, an aberrant nuclear hormone re ceptor implicated in human acute promyelocytic leukemia (APL). Arsenite ind uces clinical remission of APL through a incompletely understood mechanism. We report here that arsenite is a potent inhibitor of the interaction of S MRT with its transcription factor partners, including PML-RAR alpha. Arseni te operates, in part, through a mitogen-activated protein (MAP) kinase casc ade culminating in phosphorylation of the SMRT protein, dissociation of SMR T from its nuclear receptor partners, and a relocalization of SMRT out of t he nucleus into the cytoplasm of the cell. Conversely, inhibition of this M AP kinase cascade attenuates the effects of arsenite on APL cells. Our resu lts implicate SMRT as an important biological target for the actions of ars enite in both normal and neoplastic cells.