title: BH3-only protein Noxa contributes to apoptotic control of stress-erythropoiesis.
abstract: Apoptosis plays an essential role in the control of erythropoiesis under normal and pathological conditions. However, the contribution of individual proteins within cell death signalling pathways remains poorly defined. Here, we investigated the role of the pro-apoptotic Bcl-2 family member Noxa in the regulation of erythropoiesis. We found that expression of Noxa is induced during erythroid differentiation of human and murine precursor cells. Using in vitro model systems for erythroid progenitors, we observed rapid induction of Noxa upon cytokine deprivation. Knockdown or deletion of Noxa conferred significant protection against apoptosis upon cytokine withdrawal. In vivo, Noxa deficiency did not affect hematological blood parameters or erythroid progenitor composition of bone marrow and spleen under steady-state conditions. In contrast, in a model of acute haemolytic anemia, Noxa-deficiency enhanced hematocrit recovery. Moreover, in a model of chronic inflammation-induced anemia, Noxa-ablation resulted in a dramatic increase of erythroblast expansion. Our data indicate that induction of Noxa in erythroid progenitors sets a survival threshold that limits expansion beyond the number of cells that can be sustained by the available cytokines, which becomes apparent under conditions of induced anemia.
authors: Department of Experimental Immunology, Academic Medical Center, Meibergdreef 8, 1105 AZ, Amsterdam, The Netherlands. felix.wensveen@gmail.com.
authors: Felix M
authors: FM
authors: Wensveen
authors: Department of Experimental Immunology, Academic Medical Center, Meibergdreef 8, 1105 AZ, Amsterdam, The Netherlands.
authors: Christian R
authors: CR
authors: Geest
authors: Department of Experimental Immunology, Academic Medical Center, Meibergdreef 8, 1105 AZ, Amsterdam, The Netherlands.
authors: Sten F W M
authors: SFWM
authors: Libregts
authors: Department of Experimental Immunology, Academic Medical Center, Meibergdreef 8, 1105 AZ, Amsterdam, The Netherlands.
authors: Ingrid A M
authors: IAM
authors: Derks
authors: Division of Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC, Australia.
authors: Paul G
authors: PG
authors: Ekert
authors: Division of Developmental Immunology, BIOCENTER, Innsbruck Medical University, Innrain 80-82, 6020, Innsbruck, Austria.
authors: Verena
authors: V
authors: Labi
authors: Division of Developmental Immunology, BIOCENTER, Innsbruck Medical University, Innrain 80-82, 6020, Innsbruck, Austria.
authors: Andreas
authors: A
authors: Villunger
authors: Department of Experimental Immunology, Academic Medical Center, Meibergdreef 8, 1105 AZ, Amsterdam, The Netherlands.|Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory AMC/UvA, Amsterdam, The Netherlands.
authors: Martijn A
authors: MA
authors: Nolte
authors: Department of Experimental Immunology, Academic Medical Center, Meibergdreef 8, 1105 AZ, Amsterdam, The Netherlands.
authors: Eric
authors: E
authors: Eldering
mesh_terms: D000740:Anemia / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D010659:Phenylhydrazines; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D016207:Cytokines; D008565:Membrane Proteins; D010659:Phenylhydrazines; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C030299:phenylhydrazine
references: Curr Opin Immunol. 2007 Oct;19(5):497-502
references: 17662585
references: Blood. 2010 Jan 14;115(2):344-52
references: 19965665
references: Blood. 2007 Nov 1;110(9):3209-17
references: 17634411
references: Immunity. 2001 Nov;15(5):801-12
references: 11728341
references: PLoS One. 2011;6(7):e21192
references: 21760888
references: Blood. 2003 Mar 15;101(6):2393-400
references: 12433687
references: Science. 2003 Nov 7;302(5647):1036-8
references: 14500851
references: J Cell Physiol. 1989 Aug;140(2):323-34
references: 2663885
references: Oncogene. 2008 Dec;27 Suppl 1:S84-92
references: 19641509
references: Nat Biotechnol. 2005 Jan;23(1):69-74
references: 15619619
references: J Histochem Cytochem. 1996 Dec;44(12):1363-72
references: 8985128
references: Blood. 2012 Feb 9;119(6):1440-9
references: 22144184
references: Blood. 1961 Aug;18:187-201
references: 13779961
references: Blood. 2011 Sep 1;118(9):2578-88
references: 21725055
references: Immunol Rev. 2012 Sep;249(1):84-103
references: 22889217
references: Mol Cell. 2005 Feb 4;17(3):393-403
references: 15694340
references: Nature. 2002 Feb 21;415(6874):922-6
references: 11859372
references: Curr Opin Cell Biol. 2005 Dec;17(6):617-25
references: 16243507
references: Blood. 2001 Dec 1;98(12):3261-73
references: 11719363
references: Immunity. 2010 Jun 25;32(6):754-65
references: 20620942
references: J Exp Med. 1999 Jun 7;189(11):1691-8
references: 10359572
references: Mol Cell. 2006 Mar 17;21(6):749-60
references: 16543145
references: Blood. 2006 Sep 1;108(5):1461-8
references: 16705087
references: Mol Cell. 2010 Feb 12;37(3):299-310
references: 20159550
references: Immunity. 2006 Jun;24(6):703-716
references: 16782027
references: Br J Haematol. 1990 Nov;76(3):414-9
references: 2261351
references: Blood. 2012 Feb 2;119(5):1228-39
references: 22086418
references: Blood. 2008 Jun 1;111(11):5390-9
references: 18349318
references: Leukemia. 2004 Jul;18(7):1176-99
references: 15208642
references: Apoptosis. 2011 Jul;16(7):708-21
references: 21516346
references: Exp Hematol. 2009 Feb;37(2):151-8
references: 19100675
references: Nat Cell Biol. 2006 Dec;8(12):1348-58
references: 17115033
references: J Clin Invest. 1926 Apr;2(4):329-42
references: 16693685
references: Nucleic Acids Res. 2003 Dec 1;31(23):e153
references: 14627843
references: J Immunol. 2013 Feb 1;190(3):1180-91
references: 23277490
references: Science. 2005 Feb 18;307(5712):1101-4
references: 15718471
references: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6217-22
references: 17389404
references: Oncogene. 2007 Oct 15;26(47):6724-37
references: 17934481