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

Nature volume 401, pages 489–493 (1999)Cite this article

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.

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Figure 1: Death receptors trigger arrest of erythroid differentiation.
Figure 2: CD95-induced inhibition of erythropoiesis in the absence of cell death is reversible.
Figure 3: Anti-CD95 and mature erythroblasts induce GATA-1 downregulation and impaired erythroid differentiation.
Figure 4: GATA-1 is a target of caspases in vitro and in vivo.
Figure 5: Blockade of GATA-1 degradation protects late erythroid progenitors from death and differentiation arrest.

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Acknowledgements

We thank G. M. Cohen and X. M. Sun for the antibody against caspase-7, S. H. Orkin for GATA-1 cDNA and NF-E2 antibody, and D. Marinelli and M. Teragnoli for help with text and figures. R.D.M. and A.Z. are supported by A.I.R.C.

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  1. These authors contributed equally to the work.

Authors and Affiliations

  1. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, 19107-5541 , Pennsylvania, USA

    Ruggero De Maria, Adriana Eramo, Srinivasa M. Srinivasula, Emad S. Alnemri & Cesare Peschle

  2. Istituto di Patologia Generale, Universitá di Catania, Catania, 95124, Italy

    Ruggero De Maria & Ann Zeuner

  3. Department of Haematology and Oncology Istituto Superiore di Sanitá, Rome, 00161, Italy

    Ann Zeuner, Cristina Domenichelli, Desiree Bonci, Francesco Grignani, Ugo Testa & Cesare Peschle

  4. Istituto di Medicina Interna e Scienze Oncologiche, Universitá di Perugia, 06122, Italy

    Francesco Grignani

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  1. Ruggero De Maria
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Correspondence to Ruggero De Maria.

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De Maria, R., Zeuner, A., Eramo, A. et al. Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature 401, 489–493 (1999). https://doi.org/10.1038/46809

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