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Molecular and Cellular Biology, December 2003, p. 9375-9388, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.9375-9388.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Growth Suppression by Acute Promyelocytic Leukemia-Associated Protein PLZF Is Mediated by Repression of c-myc Expression

Melanie J. McConnell,1 Nathalie Chevallier,1 Windy Berkofsky-Fessler,1 Jena M. Giltnane,2 Rupal B. Malani,1 Louis M. Staudt,2 and Jonathan D. Licht1*

Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029,1 Metabolism Branch, National Cancer Institute, Bethesda, Maryland 208922

Received 28 March 2003/ Returned for modification 2 June 2003/ Accepted 13 September 2003

The transcriptional repressor PLZF was identified by its translocation with retinoic acid receptor alpha in t(11;17) acute promyelocytic leukemia (APL). Ectopic expression of PLZF leads to cell cycle arrest and growth suppression, while disruption of normal PLZF function is implicated in the development of APL. To clarify the function of PLZF in cell growth and survival, we used an inducible PLZF cell line in a microarray analysis to identify the target genes repressed by PLZF. One prominent gene identified was c-myc. The array analysis demonstrated that repression of c-myc by PLZF led to a reduction in c-myc-activated transcripts and an increase in c-myc-repressed transcripts. Regulation of c-myc by PLZF was shown to be both direct and reversible. An interaction between PLZF and the c-myc promoter could be detected both in vitro and in vivo. PLZF repressed the wild-type c-myc promoter in a reporter assay, dependent on the integrity of the binding site identified in vitro. PLZF binding in vivo was coincident with a decrease in RNA polymerase occupation of the c-myc promoter, indicating that repression occurred via a reduction in the initiation of transcription. Finally, expression of c-myc reversed the cell cycle arrest induced by PLZF. These data suggest that PLZF expression maintains a cell in a quiescent state by repressing c-myc expression and preventing cell cycle progression. Loss of this repression through the translocation that occurs in t(11;17) would have serious consequences for cell growth control.

* Corresponding author. Mailing address: Box 1130, Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Pl., New York, NY 10029. Phone: (212) 659-5487. Fax: (212) 849-2523. E-mail: Jonathan.licht{at}mssm.edu.

Molecular and Cellular Biology, December 2003, p. 9375-9388, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.9375-9388.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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