title: Bcl-x(L) prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin.
abstract: The long form of B-cell lymphoma-x (Bcl-x(L)), an outer mitochondrial membrane protein, has been proposed to mediate the antiapoptotic action of erythropoietin on erythroid progenitor cells and to be necessary for heme synthesis in erythroblasts. Mice with conditional knockout of Bcl-x(L) (conditional bcl-x(-/-) mice) develop severe anemia that has been attributed to hemolysis and is accompanied by splenomegaly. We characterized further the anemia of conditional bcl-x(-/-) mice and investigated the role of Bcl-x(L) in the action of erythropoietin and in heme synthesis. We analyzed peripheral blood cells and cultured splenic erythroblasts of conditional bcl-x(-/-) mice and littermates that were rendered anemic by bleeding. Although they had massive splenic erythroblastosis, conditional bcl-x(-/-) mice had decreased circulating reticulocytes compared to littermates even prior to bleeding the littermates. Compared to erythroblasts of bled littermates, bcl-x(-/-) erythroblasts cultured with erythropoietin underwent apoptosis during the later, hemoglobin-synthesizing stages of differentiation. The bcl-x(-/-) erythroblasts synthesized heme, but at reduced rates compared to bled littermate erythroblasts. When cultured without erythropoietin, bcl-x(-/-) erythroblasts underwent apoptosis at early stages of differentiation, prior to hemoglobin synthesis. Bcl-x(L) is not required for heme synthesis and does not mediate the antiapoptotic effects of erythropoietin, but it prevents ineffective erythropoiesis due to apoptosis in late-stage, hemoglobin-synthesizing erythroblasts.
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center , Nashville, TN 37212, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Rhodes
authors.forename: Prapaporn
authors.initials: P
authors.lastname: Kopsombut
authors.forename: Maurice C
authors.initials: MC
authors.lastname: Bondurant
authors.forename: James O
authors.initials: JO
authors.lastname: Price
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Koury
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004900:Erythroblasts / Q000166:cytology / Q000187:drug effects*; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology*; D006418:Heme / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology*; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D004921:Erythropoietin; D006418:Heme