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Molecular and Cellular Biology, December 1999, p. 7961-7971, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Independent Repressor Domains in ZEB Regulate Muscle and T-Cell Differentiation

Antonio A. Postigo and Douglas C. Dean*

Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri 63110

Received 5 February 1999/Returned for modification 5 March 1999/Accepted 30 August 1999

ZEB is a zinc finger-homeodomain protein that represses transcription by binding to a subset of E-box sequences. ZEB inhibits muscle differentiation in mammalian systems, and its Drosophila orthologue, zfh-1, inhibits somatic and cardiac muscle differentiation during Drosophila embryogenesis. ZEB also binds to the promoter of pivotal hematopoietic genes (including those encoding interleukin-2, CD4, GATA-3, and alpha 4-integrin), and mice in which ZEB has been genetically targeted show thymic atrophy, severe defects in lymphocyte differentiation, and increased expression of the alpha 4-integrin and CD4. Here, we demonstrate that ZEB contains separate repressor domains which function in T lymphocytes and muscle, respectively. The most C-terminal domain inhibits muscle differentiation in mammalian cells by specifically blocking the transcriptional activity of the myogenic factor MEF2C. The more N-terminal domain blocks activity of hematopoietic transcription factors such as c-myb, members of the ets family, and TFE-III. Our results demonstrate that ZEB has evolved with two independent repressor domains which target distinct sets of transcription factors and function in different tissues.

* Corresponding author. Mailing address: Division of Molecular Oncology, Washington University School of Medicine, Box 8069, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 362 8989. Fax: (314) 747 2797. E-mail: ddean{at}im.wustl.edu.

Molecular and Cellular Biology, December 1999, p. 7961-7971, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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