c-Myb and Ets proteins synergize to overcome transcriptional repression by ZEB.
The Zfh family of zinc finger/homeodomain proteins was first identified in Drosophila where it is required for differentiation of tissues such as the central nervous system and muscle. ZEB, a vertebrate homolog of Zfh-1, binds a subset of E boxes and blocks myogenesis through transcriptional repression of muscle genes. We present evidence here that ZEB also has an important role in controlling hematopoietic gene transcription. Two families of transcription factors that are required for normal hematopoiesis are c-Myb and Ets. These factors act synergistically to activate transcription, and this synergy is required for transcription of at least several important hematopoietic genes. ZEB blocks the activity of c-Myb and Ets individually, but together the factors synergize to resist this repression. Such repression imposes a requirement for both c-Myb and Ets for transcriptional activity, providing one explanation for why synergy between these factors is important. The balance between repression by ZEB and transcriptional activation by c-Myb/Ets provides a flexible regulatory mechanism for controlling gene expression in hematopoietic cells. We demonstrate that one target of this positive/negative regulation in vivo is the alpha4 integrin, which play a key role in normal hematopoiesis and function of mature leukocytes.
Postigo
A A
AA
Department of Medicine and Cell Biology, Washington University School of Medicine, St Louis, MO 63110, USA.
Sheppard
A M
AM
Mucenski
M L
ML
Dean
D C
DC
D015703:Antigens, CD / Q000235:genetics*; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D018398:Homeodomain Proteins; D006801:Humans; D039441:Integrin alpha4; D019169:Jurkat Cells; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D020598:Proto-Oncogene Proteins c-myb; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000502:physiology*; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000071799:Zinc Finger E-box-Binding Homeobox 1; D016335:Zinc Fingers
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D020598:Proto-Oncogene Proteins c-myb; D012097:Repressor Proteins; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; D015534:Trans-Activators; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C081010:zfh1 protein, Drosophila; D039441:Integrin alpha4