| Autor: |
Bullock GC; Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Delehanty LL, Talbot AL, Gonias SL, Tong WH, Rouault TA, Dewar B, Macdonald JM, Chruma JJ, Goldfarb AN |
| Jazyk: |
angličtina |
| Zdroj: |
Blood [Blood] 2010 Jul 08; Vol. 116 (1), pp. 97-108. Date of Electronic Publication: 2010 Apr 20. |
| DOI: |
10.1182/blood-2009-10-251496 |
| Abstrakt: |
Human red cell differentiation requires the action of erythropoietin on committed progenitor cells. In iron deficiency, committed erythroid progenitors lose responsiveness to erythropoietin, resulting in hypoplastic anemia. To address the basis for iron regulation of erythropoiesis, we established primary hematopoietic cultures with transferrin saturation levels that restricted erythropoiesis but permitted granulopoiesis and megakaryopoiesis. Experiments in this system identified as a critical regulatory element the aconitases, multifunctional iron-sulfur cluster proteins that metabolize citrate to isocitrate. Iron restriction suppressed mitochondrial and cytosolic aconitase activity in erythroid but not granulocytic or megakaryocytic progenitors. An active site aconitase inhibitor, fluorocitrate, blocked erythroid differentiation in a manner similar to iron deprivation. Exogenous isocitrate abrogated the erythroid iron restriction response in vitro and reversed anemia progression in iron-deprived mice. The mechanism for aconitase regulation of erythropoiesis most probably involves both production of metabolic intermediates and modulation of erythropoietin signaling. One relevant signaling pathway appeared to involve protein kinase Calpha/beta, or possibly protein kinase Cdelta, whose activities were regulated by iron, isocitrate, and erythropoietin. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
