期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 21, 期 21, 页码 7172-7182出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.21.21.7172-7182.2001
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资金
- NCI NIH HHS [R37 CA053394, R37 CA-53394] Funding Source: Medline
- NIDDK NIH HHS [R01 DK-53528, R01 DK053528] Funding Source: Medline
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 receptor implicated in human acute promyelocytic leukemia (APL). Arsenite induces clinical remission of APL through a incompletely understood mechanism. We report here that arsenite is a potent inhibitor of the interaction of SMRT with its transcription factor partners, including PML-RAR alpha. Arsenite operates, in part, through a mitogen-activated protein (MAP) kinase cascade culminating in phosphorylation of the SMRT protein, dissociation of SMRT from its nuclear receptor partners, and a relocalization of SMRT out of the nucleus into the cytoplasm of the cell. Conversely, inhibition of this MAP kinase cascade attenuates the effects of arsenite on APL cells. Our results implicate SMRT as an important biological target for the actions of arsenite in both normal and neoplastic cells.
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