Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1

The production of red blood cells follows the sequential formation of proer ythroblasts and basophilic, polychromatophilic and orthochromatic erythrobl asts, and is promoted by the hormone erythropoietin (Epo) in response to ti ssue hypoxia(1). However, little is known about the negative regulation of this process(2). Death receptors are a family of surface molecules that tri gger caspase activation and apoptosis in a variety of cell types(3-5). Here we show that immature erythroid cells express several death receptors whos e ligands are produced by mature erythroblasts. Exposure of erythroid proge nitors to mature erythroblasts or death-receptor ligands resulted in caspas e-mediated degradation of the transcription factor GATA-1, which is associa ted with impaired erythroblast development. Expression of a caspase-resista nt GATA-1 mutant, but not of the wild-type gene, completely restored erythr oid expansion and differentiation following the triggering of death recepto rs, indicating that there is regulatory feedback between mature and immatur e erythroblasts through caspase-mediated cleavage of GATA-1. Similarly, ery thropoiesis blockade following Epo deprivation was largely prevented by the expression of caspase-inhibitory proteins or caspase-resistant GATA-1 in e rythroid progenitors. Caspase-mediated cleavage of GATA-1 may therefore rep resent an important negative control mechanism in erythropoiesis.