1: Mol Cell Biol. 1999 Dec;19(12):7961-71. 

Independent repressor domains in ZEB regulate muscle and T-cell differentiation.

Postigo AA, Dean DC.

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

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.

PMID: 10567522 [PubMed - indexed for MEDLINE]


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2: EMBO J. 1997 Jul 1;16(13):3924-34. 

c-Myb and Ets proteins synergize to overcome transcriptional repression by ZEB.

Postigo AA, Sheppard AM, Mucenski ML, Dean DC.

Department of Medicine and Cell Biology, Washington University School of
Medicine, St Louis, MO 63110, USA.

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.

PMID: 9233802 [PubMed - indexed for MEDLINE]


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