期刊
BLOOD
卷 111, 期 11, 页码 5390-5399出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-10-119743
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资金
- NCRR NIH HHS [P20 RR015555, P20-RR015555, P20 RR018789, P20-RR018789] Funding Source: Medline
- NHLBI NIH HHS [R01-HL44491, R01 HL044491] Funding Source: Medline
EPO functions primarily as an erythroblast survival factor, and its antiapoptotic actions have been proposed to involve predominantly P13-kinase and BCL-X pathways. Presently, the nature of EPO-regulated survival genes has been investigated through transcriptome analyses of highly responsive, primary bone marrow erythroblasts. Two proapoptotic factors, Bim and FoxO3a, were rapidly repressed not only via the wild-type EPOR, but also by PY-deficient knocked-in EPOR alleles. In parallel, Pim1 and Pim3 kinases and Irs2 were induced. For this survival gene set, induction failed via a PY-null EPOR-HIM allele, but was restored upon reconstitution of a PY343 STAT5-binding site within a related EPOR-H allele. Notably, EPOR-HM supports erythropoiesis at steady state but not during anemia, while EPOR-H exhibits near wildtype EPOR activities. EPOR-H and the wild-type EPOR (but not EPOR-HIM) also markedly stimulated the expression of Trb3 pseudokinase, and intracellular serpin, Serpina-3G. For SERPINA-3G and TRB3, ectopic expression in EPO-dependent progenitors furthermore significantly inhibited apoptosis due to cytokine withdrawal. BCL-XL and BCL2 also were studied, but in highly responsive Kit(pos)CD71(high)Ter119(neg) erythroblasts, neither was EPO modulated. EPOR survival circuits therefore include the repression of Bim plus FoxO3a, and EPOR/PY343/ STAT5-dependent stimulation of Pim1, Pim3, Irs2 plus Serpina-3G, and Trb3 as new antiapoptotic effectors.
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