GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-xL expression.
The transcription factor GATA-1 is essential for normal erythropoiesis. By examining in vitro-differentiated embryonic stem cells, we showed previously that in the absence of GATA-1, committed erythroid precursors fail to complete maturation and instead undergo apoptosis. The mechanisms by which GATA-1 controls cell survival are unknown. Here we report that in erythroid cells, GATA-1 strongly induces the expression of the anti-apoptotic protein bcl-xL, but not the related proteins bcl-2 and mcl-1. Consistent with a role for bcl-xL in mediating GATA-1-induced erythroid cell survival, in vitro-differentiated bcl-xL-/- embryonic stem cells fail to generate viable mature definitive erythroid cells, a phenotype resembling that of GATA-1 gene disruption. In addition, we show that erythropoietin, which is also required for erythroid cell survival, cooperates with GATA-1 to stimulate bcl-xL gene expression and to maintain erythroid cell viability during terminal maturation. Together, our data show that bcl-xL is essential for normal erythroid development and suggest a regulatory hierarchy in which bcl-xL is a critical downstream effector of GATA-1 and erythropoietin-mediated signals.
Gregory
T
T
Ontogeny, Inc, Cambridge, MA 02138-1118, USA.
Yu
C
C
Ma
A
A
Orkin
S H
SH
Blobel
G A
GA
Weiss
M J
MJ
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D004900:Erythroblasts / Q000166:cytology / Q000502:physiology*; D050981:Erythroid-Specific DNA-Binding Factors; D004920:Erythropoiesis / Q000502:physiology; D004921:Erythropoietin / Q000494:pharmacology / Q000502:physiology*; D050982:GATA1 Transcription Factor; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051020:bcl-X Protein; D004921:Erythropoietin