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

Ruggero De Maria (), Ann Zeuner, Adriana Eramo, Cristina Domenichelli, Desiree Bonci, Francesco Grignani, Srinivasa M. Srinivasula, Emad S. Alnemri, Ugo Testa and Cesare Peschle
Additional contact information
Ruggero De Maria: Kimmel Cancer Center, Thomas Jefferson University
Ann Zeuner: Istituto di Patologia Generale, Universitá di Catania
Adriana Eramo: Kimmel Cancer Center, Thomas Jefferson University
Cristina Domenichelli: Department of Haematology and Oncology Istituto Superiore di Sanitá
Desiree Bonci: Department of Haematology and Oncology Istituto Superiore di Sanitá
Francesco Grignani: Department of Haematology and Oncology Istituto Superiore di Sanitá
Srinivasa M. Srinivasula: Kimmel Cancer Center, Thomas Jefferson University
Emad S. Alnemri: Kimmel Cancer Center, Thomas Jefferson University
Ugo Testa: Department of Haematology and Oncology Istituto Superiore di Sanitá
Cesare Peschle: Kimmel Cancer Center, Thomas Jefferson University

Nature, 1999, vol. 401, issue 6752, 489-493

Abstract: Abstract 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 hypoxia1. However, little is known about the negative regulation of this process2. Death receptors are a family of surface molecules that trigger caspase activation and apoptosis in a variety of cell types3,4,5. 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.

Date: 1999
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DOI: 10.1038/46809

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