Repression of c-kit and its downstream substrates by GATA-1 inhibits cell proliferation during erythroid maturation.
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.
Munugalavadla
Veerendra
V
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Cancer Research Institute, 1044 W. Walnut Street, Room 425, Indianapolis, IN 46202, USA. vmunugal@iupui.edu
Dore
Louis C
LC
Tan
Bai Lin
BL
Hong
Li
L
Vishnu
Melanie
M
Weiss
Mitchell J
MJ
Kapur
Reuben
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002999:Clone Cells; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D041905:Erythroid Cells / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D050981:Erythroid-Specific DNA-Binding Factors; D004921:Erythropoietin / Q000378:metabolism; D050982:GATA1 Transcription Factor; D005786:Gene Expression Regulation / Q000502:physiology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D019089:Stem Cell Factor / Q000378:metabolism; D013379:Substrate Specificity; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D006131:Growth Inhibitors; D012097:Repressor Proteins; D019089:Stem Cell Factor; D014157:Transcription Factors; D004921:Erythropoietin; D019009:Proto-Oncogene Proteins c-kit; D019061:src-Family Kinases