A GATA-2/estrogen receptor chimera functions as a ligand-dependent negative regulator of self-renewal.

2.50
Hdl Handle:
http://hdl.handle.net/10541/91381
Title:
A GATA-2/estrogen receptor chimera functions as a ligand-dependent negative regulator of self-renewal.
Authors:
Heyworth, Clare M; Gale, Karin; Dexter, T Michael; May, Gillian; Enver, Tariq
Abstract:
The transcription factor GATA-2 is expressed in hematopoietic stem and progenitor cells and is functionally implicated in their survival and proliferation. We have used estrogen and tamoxifen-inducible forms of GATA-2 to modulate the levels of GATA-2 in the IL-3-dependent multipotential hematopoietic progenitor cell model FDCP mix. Ligand-dependent induction of exogenous GATA-2 activity did not rescue cells deprived of IL-3 from apoptosis. However, induction of GATA-2 activity in cells cultured in IL-3 blocked factor-dependent self-renewal but not factor-dependent survival: Cells undergo cell cycle arrest and cease proliferating but do not apoptose. This was accompanied by differentiation down the monocytic and granulocytic pathways. Differentiation occurred in the presence of IL-3 and did not require addition of exogenous differentiation growth factors such as G-CSF or GM-CSF normally required to induce granulomonocytic differentiation of FDCP-mix cells. Conversely, EPO-dependent erythroid differentiation was inhibited by GATA-2 activation. These biological effects were obtained with levels of exogenous GATA-2 representing less than twofold increases over endogenous GATA-2 levels and were not observed in cells overexpressing GATA-1/ER. Similar effects on proliferation and differentiation were also observed in primary progenitor cells, freshly isolated from murine bone marrow and transduced with a GATA-2/ER-containing retrovirus. Taken together, these data suggest that threshold activities of GATA-2 in hematopoietic progenitor cells are a critical determinant in influencing self-renewal versus differentiation outcomes.
Affiliation:
Cancer Research Campaign (CRC) Section of Hematopoietic Cell and Gene Therapeutics, Paterson Institute for Cancer Research, Christie Hospital National Health Service Trust, Manchester M20 4BX, UK.
Citation:
A GATA-2/estrogen receptor chimera functions as a ligand-dependent negative regulator of self-renewal. 1999, 13 (14):1847-60 Genes Dev.
Journal:
Genes & Development
Issue Date:
15-Jul-1999
URI:
http://hdl.handle.net/10541/91381
PubMed ID:
10421636
Type:
Article
Language:
en
ISSN:
0890-9369
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorHeyworth, Clare Men
dc.contributor.authorGale, Karinen
dc.contributor.authorDexter, T Michaelen
dc.contributor.authorMay, Gillianen
dc.contributor.authorEnver, Tariqen
dc.date.accessioned2010-02-08T11:41:40Z-
dc.date.available2010-02-08T11:41:40Z-
dc.date.issued1999-07-15-
dc.identifier.citationA GATA-2/estrogen receptor chimera functions as a ligand-dependent negative regulator of self-renewal. 1999, 13 (14):1847-60 Genes Dev.en
dc.identifier.issn0890-9369-
dc.identifier.pmid10421636-
dc.identifier.urihttp://hdl.handle.net/10541/91381-
dc.description.abstractThe transcription factor GATA-2 is expressed in hematopoietic stem and progenitor cells and is functionally implicated in their survival and proliferation. We have used estrogen and tamoxifen-inducible forms of GATA-2 to modulate the levels of GATA-2 in the IL-3-dependent multipotential hematopoietic progenitor cell model FDCP mix. Ligand-dependent induction of exogenous GATA-2 activity did not rescue cells deprived of IL-3 from apoptosis. However, induction of GATA-2 activity in cells cultured in IL-3 blocked factor-dependent self-renewal but not factor-dependent survival: Cells undergo cell cycle arrest and cease proliferating but do not apoptose. This was accompanied by differentiation down the monocytic and granulocytic pathways. Differentiation occurred in the presence of IL-3 and did not require addition of exogenous differentiation growth factors such as G-CSF or GM-CSF normally required to induce granulomonocytic differentiation of FDCP-mix cells. Conversely, EPO-dependent erythroid differentiation was inhibited by GATA-2 activation. These biological effects were obtained with levels of exogenous GATA-2 representing less than twofold increases over endogenous GATA-2 levels and were not observed in cells overexpressing GATA-1/ER. Similar effects on proliferation and differentiation were also observed in primary progenitor cells, freshly isolated from murine bone marrow and transduced with a GATA-2/ER-containing retrovirus. Taken together, these data suggest that threshold activities of GATA-2 in hematopoietic progenitor cells are a critical determinant in influencing self-renewal versus differentiation outcomes.en
dc.language.isoenen
dc.subjectOestrogen Receptorsen
dc.subject.meshAnimals-
dc.subject.meshBase Sequence-
dc.subject.meshCell Differentiation-
dc.subject.meshCell Line-
dc.subject.meshCell Lineage-
dc.subject.meshDNA Primers-
dc.subject.meshDNA-Binding Proteins-
dc.subject.meshErythroid-Specific DNA-Binding Factors-
dc.subject.meshGATA1 Transcription Factor-
dc.subject.meshGATA2 Transcription Factor-
dc.subject.meshGene Expression Regulation, Developmental-
dc.subject.meshLigands-
dc.subject.meshMice-
dc.subject.meshReceptors, Estrogen-
dc.subject.meshRecombinant Fusion Proteins-
dc.subject.meshTranscription Factors-
dc.titleA GATA-2/estrogen receptor chimera functions as a ligand-dependent negative regulator of self-renewal.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign (CRC) Section of Hematopoietic Cell and Gene Therapeutics, Paterson Institute for Cancer Research, Christie Hospital National Health Service Trust, Manchester M20 4BX, UK.en
dc.identifier.journalGenes & Developmenten

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