Independent repressor domains in ZEB regulate muscle and T-cell differentiation.
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.
Postigo
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Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Dean
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D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000502:physiology; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D051379:Mice; D009132:Muscles / Q000166:cytology*; D018006:Myogenic Regulatory Factors / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000071799:Zinc Finger E-box-Binding Homeobox 1; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D020598:Proto-Oncogene Proteins c-myb; D012097:Repressor Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C081010:zfh1 protein, Drosophila; D006655:Histone Deacetylases