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Repression of c-Kit and Its Downstream Substrates by GATA-1 Inhibits Cell Proliferation during Erythroid Maturation
- Source :
- Molecular and Cellular Biology. 25:6747-6759
- Publication Year :
- 2005
- Publisher :
- Informa UK Limited, 2005.
-
Abstract
- Stem cell factor (SCF), erythropoietin (Epo), and GATA-1 play an essential role(s) in erythroid development. We examined how these proteins interact functionally in G1E cells, a GATA-1(-) erythroblast line that proliferates in an SCF-dependent fashion and, upon restoration of GATA-1 function, undergoes GATA-1 proliferation arrest and Epo-dependent terminal maturation. We show that SCF-induced cell cycle progression is mediated via activation of the Src kinase/c-Myc pathway. Restoration of GATA-1 activity induced G1 cell cycle arrest coincident with repression of c-Kit and its downstream effectors Vav1, Rac1, and Akt. Sustained expression of each of these individual signaling components inhibited GATA-1-induced cell cycle arrest to various degrees but had no effects on the expression of GATA-1-regulated erythroid maturation markers. Chromatin immunoprecipitation analysis revealed that GATA-1 occupies a defined Kit gene regulatory element in vivo, suggesting a direct mechanism for gene repression. Hence, in addition to its well-established function as an activator of erythroid genes, GATA-1 also participates in a distinct genetic program that inhibits cell proliferation by repressing the expression of multiple components of the c-Kit signaling axis. Our findings reveal a novel aspect of molecular cross talk between essential transcriptional and cytokine signaling components of hematopoietic development.
- Subjects :
- Cell cycle checkpoint
Cellular differentiation
Gene Expression
Apoptosis
Stem cell factor
Biology
Substrate Specificity
Mice
Erythroid Cells
Animals
GATA1 Transcription Factor
Erythropoietin
Molecular Biology
Protein kinase B
Cell Line, Transformed
Cell Proliferation
Stem Cell Factor
Cell growth
Cell Differentiation
Cell Biology
Molecular biology
Growth Inhibitors
Clone Cells
Cell biology
DNA-Binding Proteins
Repressor Proteins
Proto-Oncogene Proteins c-kit
src-Family Kinases
Gene Expression Regulation
embryonic structures
Erythroid-Specific DNA-Binding Factors
Signal transduction
G1 phase
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 10985549
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Molecular and Cellular Biology
- Accession number :
- edsair.doi.dedup.....5096a417f869a2aa93030430275e688e