Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1.
The production of red blood cells follows the sequential formation of proerythroblasts and basophilic, polychromatophilic and orthochromatic erythroblasts, and is promoted by the hormone erythropoietin (Epo) in response to tissue hypoxia. However, little is known about the negative regulation of this process. Death receptors are a family of surface molecules that trigger caspase activation and apoptosis in a variety of cell types. Here we show that immature erythroid cells express several death receptors whose ligands are produced by mature erythroblasts. Exposure of erythroid progenitors to mature erythroblasts or death-receptor ligands resulted in caspase-mediated degradation of the transcription factor GATA-1, which is associated with impaired erythroblast development. Expression of a caspase-resistant GATA-1 mutant, but not of the wild-type gene, completely restored erythroid expansion and differentiation following the triggering of death receptors, indicating that there is regulatory feedback between mature and immature erythroblasts through caspase-mediated cleavage of GATA-1. Similarly, erythropoiesis blockade following Epo deprivation was largely prevented by the expression of caspase-inhibitory proteins or caspase-resistant GATA-1 in erythroid progenitors. Caspase-mediated cleavage of GATA-1 may therefore represent an important negative control mechanism in erythropoiesis.
De Maria
R
R
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-5541, USA. rdemaria@lac.jci.tju.edu
Zeuner
A
A
Eramo
A
A
Domenichelli
C
C
Bonci
D
D
Grignani
F
F
Srinivasula
S M
SM
Alnemri
E S
ES
Testa
U
U
Peschle
C
C
D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation; D004900:Erythroblasts / Q000502:physiology; D050981:Erythroid-Specific DNA-Binding Factors; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000502:physiology; D053222:Fas Ligand Protein; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology; D016296:Mutagenesis; D009154:Mutation; D011956:Receptors, Cell Surface / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D019014:fas Receptor; D004921:Erythropoietin; D020169:Caspases