Attenuation of EPO-dependent erythroblast formation by death-associated protein kinase-2.
The adult erythron is maintained via dynamic modulation of erythroblast survival potentials. Toward identifying novel regulators of this process, murine splenic erythroblasts at 3 developmental stages were prepared, purified and profiled. Stage-to-stage modulated genes were then functionally categorized, with a focus on apoptotic factors. In parallel with BCL-X and NIX, death-associated protein kinase-2 (DAPK2) was substantially up-modulated during late erythropoiesis. Among hematopoietic lineages, DAPK2 was expressed predominantly in erythroid cells. In a Gata1-IE3.9int-DAPK2 transgenic mouse model, effects on steady-state reticulocyte and red blood cell (RBC) levels were limited. During hemolytic anemia, however, erythropoiesis was markedly deficient. Ex vivo ana-lyses revealed heightened apoptosis due to DAPK2 at a Kit(-)CD71(high)Ter119(-) stage, together with a subsequent multifold defect in late-stage Kit(-)CD71(high)Ter119(+) cell formation. In UT7epo cells, siRNA knock-down of DAPK2 enhanced survival due to cytokine withdrawal, and DAPK2's phosphorylation and kinase activity also were erythropoietin (EPO)-modulated. DAPK2 therefore comprises a new candidate attenuator of stress erythropoiesis.
Stem and Progenitor Cell Biology Program, Molecular Medicine Division, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA.
Jing
J
Fang
Madhu
M
Menon
Diya
D
Zhang
Bruce
B
Torbett
Leif
L
Oxburgh
Mario
M
Tschan
Estelle
E
Houde
Don M
DM
Wojchowski
D000743:Anemia, Hemolytic; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D019070:Cell Lineage; D064550:Death-Associated Protein Kinases; D004900:Erythroblasts / Q000166:cytology*; D004920:Erythropoiesis / Q000235:genetics*; D004921:Erythropoietin / Q000494:pharmacology*; D006487:Hemostasis; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D015854:Up-Regulation / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D004921:Erythropoietin; D064550:Death-Associated Protein Kinases; C579103:dapk2 protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases