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Molecular and Cellular Biology, November 2001, p. 7172-7182, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7172-7182.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Arsenic Trioxide Is a Potent Inhibitor of the Interaction of SMRT Corepressor with Its Transcription Factor Partners, Including the PML-Retinoic Acid Receptor alpha  Oncoprotein Found in Human Acute Promyelocytic Leukemia

Suk-Hyun Hong, Zhihong Yang, and Martin L. Privalsky*

Section of Microbiology, Division of Biological Sciences, University of California at Davis, Davis, California 95616

Received 30 March 2001/Returned for modification 11 May 2001/Accepted 8 August 2001

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  (RARalpha ) 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-RARalpha . 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.

* Corresponding author. Mailing address: Section of Microbiology, Division of Biological Sciences, University of California at Davis, Davis, California 95616. Phone: (530) 752-3013. Fax: (530) 752-9014. E-mail: mlprivalsky{at}ucdavis.edu.

Molecular and Cellular Biology, November 2001, p. 7172-7182, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7172-7182.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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