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

S. H. Hong, Z. Yang, M. L. Privalsky

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52 Citations (Scopus)

Abstract

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 α (RARα) 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-RARα. 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.

Original languageEnglish (US)
Pages (from-to)7172-7182
Number of pages11
JournalMolecular and Cellular Biology
Volume21
Issue number21
DOIs
StatePublished - 2001

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Nuclear Receptor Co-Repressor 2
Acute Promyelocytic Leukemia
Retinoic Acid Receptors
Oncogene Proteins
Transcription Factors
Cytoplasmic and Nuclear Receptors
Mitogen-Activated Protein Kinases
Vertebrates
Cytoplasm
Phosphorylation
arsenite
arsenic trioxide

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

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title = "Arsenic trioxide is a potent inhibitor of the interaction of SMRT corepressor with its transcription factor partners, including the PML-retinoic acid receptor α oncoprotein found in human acute promyelocytic leukemia",
abstract = "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 α (RARα) 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-RARα. 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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AU - Privalsky, M. L.

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