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Molecular and Cellular Biology, April 2001, p. 2259-2268, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2259-2268.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Growth Suppressor PML Represses Transcription by Functionally and Physically Interacting with Histone Deacetylases

Wen-Shu Wu,1 Sadeq Vallian,1,dagger Edward Seto,2 Wen-Ming Yang,2 Diane Edmondson,3 Sharon Roth,3 and Kun-Sang Chang1,*

Departments of Molecular Pathology1 and Biochemistry and Molecular Biology,3 The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and The H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 336122

Received 22 September 2000/Returned for modification 2 November 2000/Accepted 9 January 2001

The growth suppressor promyelocytic leukemia protein (PML) is disrupted by the chromosomal translocation t(15;17) in acute promyelocytic leukemia (APL). PML plays a key role in multiple pathways of apoptosis and regulates cell cycle progression. The present study demonstrates that PML represses transcription by functionally and physically interacting with histone deacetylase (HDAC). Transcriptional repression mediated by PML can be inhibited by trichostatin A, a specific inhibitor of HDAC. PML coimmunoprecipitates a significant level of HDAC activity in several cell lines. PML is associated with HDAC in vivo and directly interacts with HDAC in vitro. The fusion protein PML-RARalpha encoded by the t(15;17) breakpoint interacts with HDAC poorly. PML interacts with all three isoforms of HDAC through specific domains, and its expression deacetylates histone H3 in vivo. Together, the results of our study show that PML modulates histone deacetylation and that loss of this function in APL alters chromatin remodeling and gene expression. This event may contribute to the development of leukemia.

* Corresponding author. Mailing address: Department of Molecular Pathology, Box 054, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 792-2581. Fax: (713) 792-4840. E-mail: kchang{at}mail.mdanderson.org.

dagger Present address: Division of Genetics, Department of Biology, Faculty of Science, Isfahan University, Isfahan, Iran.

Molecular and Cellular Biology, April 2001, p. 2259-2268, Vol. 21, No. 7
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.7.2259-2268.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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