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, Cesare Peschle

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)489-493
Number of pages5
JournalNature
Volume401
Issue number6752
DOIs
Publication statusPublished - Sep 30 1999

ASJC Scopus subject areas

  • General

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