title: Contrasting dynamic responses in vivo of the Bcl-xL and Bim erythropoietic survival pathways.
abstract: Survival signaling by the erythropoietin (Epo) receptor (EpoR) is essential for erythropoiesis and for its acceleration in hypoxic stress. Several apparently redundant EpoR survival pathways were identified in vitro, raising the possibility of their functional specialization in vivo. Here we used mouse models of acute and chronic stress, including a hypoxic environment and β-thalassemia, to identify two markedly different response dynamics for two erythroblast survival pathways in vivo. Induction of the antiapoptotic protein Bcl-x(L) is rapid but transient, while suppression of the proapoptotic protein Bim is slower but persistent. Similar to sensory adaptation, however, the Bcl-x(L) pathway "resets," allowing it to respond afresh to acute stress superimposed on a chronic stress stimulus. Using "knock-in" mouse models expressing mutant EpoRs, we found that adaptation in the Bcl-x(L) response occurs because of adaptation of its upstream regulator Stat5, both requiring the EpoR distal cytoplasmic domain. We conclude that survival pathways show previously unsuspected functional specialization for the acute and chronic phases of the stress response. Bcl-x(L) induction provides a "stop-gap" in acute stress, until slower but permanent pathways are activated. Furthermore, pathologic elevation of Bcl-x(L) may be the result of impaired adaptation, with implications for myeloproliferative disease mechanisms.
authors.affiliation: Departments of Pediatrics and Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Koulnis
authors.forename: Ermelinda
authors.initials: E
authors.lastname: Porpiglia
authors.forename: P Alberto
authors.initials: PA
authors.lastname: Porpiglia
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Kelly
authors.initials: K
authors.lastname: Hallstrom
authors.forename: Daniel
authors.initials: D
authors.lastname: Hidalgo
authors.forename: Merav
authors.initials: M
authors.lastname: Socolovsky
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival / Q000235:genetics; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000502:physiology*; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C494812:Bcl2l1 protein, mouse; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D051020:bcl-X Protein
references.citation: Mol Cell Biol. 2004 Sep;24(18):8037-47
references.pmid: 15340066
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8324-8
references.pmid: 8710869
references.citation: Cancer Cell. 2007 Aug;12(2):97-9
references.pmid: 17692799
references.citation: J Physiol. 1964 Mar;170:344-54
references.pmid: 14165170
references.citation: Trends Cell Biol. 2008 Apr;18(4):157-64
references.pmid: 18314333
references.citation: Blood. 2008 Sep 1;112(5):2071-80
references.pmid: 18552213
references.citation: Eur J Biochem. 1992 Dec 15;210(3):649-63
references.pmid: 1483451
references.citation: J Vis Exp. 2011 Aug 05;(54):
references.pmid: 21847081
references.citation: Leuk Res. 2008 Oct;32(10):1638-40
references.pmid: 18440067
references.citation: J Biol Chem. 2004 Jan 9;279(2):821-4
references.pmid: 14607831
references.citation: Blood. 2005 Jan 15;105(2):552-61
references.pmid: 15213094
references.citation: Blood. 2001 Dec 1;98(12):3261-73
references.pmid: 11719363
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17413-8
references.pmid: 19805084
references.citation: Blood. 2010 May 6;115(18):3686-94
references.pmid: 20223923
references.citation: Exp Hematol. 2011 Apr;39(4):434-45
references.pmid: 21291953
references.citation: J Exp Med. 1999 Jun 7;189(11):1691-8
references.pmid: 10359572
references.citation: Blood. 1999 Jul 1;94(1):87-96
references.pmid: 10381501
references.citation: Mol Cell Biol. 2004 Jul;24(14):6172-83
references.pmid: 15226421
references.citation: Blood. 1997 Jul 15;90(2):630-40
references.pmid: 9226163
references.citation: Mol Cell Biol. 2001 Feb;21(3):854-64
references.pmid: 11154272
references.citation: Mod Pathol. 2007 Sep;20(9):929-35
references.pmid: 17643100
references.citation: PLoS Biol. 2007 Oct;5(10):e252
references.pmid: 17896863
references.citation: Cell. 1999 Jul 23;98(2):181-91
references.pmid: 10428030
references.citation: Curr Opin Hematol. 2007 May;14(3):215-24
references.pmid: 17414210
references.citation: Br J Haematol. 2008 May;141(4):504-11
references.pmid: 18318760
references.citation: Blood. 1996 Sep 1;88(5):1576-82
references.pmid: 8781412
references.citation: Neuron. 2002 Feb 28;33(5):751-63
references.pmid: 11879652
references.citation: Blood. 2006 Jul 1;108(1):123-33
references.pmid: 16527892
references.citation: N Engl J Med. 1998 Feb 26;338(9):564-71
references.pmid: 9475763
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4649-53
references.pmid: 10781070
references.citation: PLoS Biol. 2010 Sep 21;8(9):
references.pmid: 20877475
references.citation: Blood Cells. 1987;13(1-2):207-16
references.pmid: 3663951
references.citation: Blood. 2003 May 1;101(9):3436-43
references.pmid: 12506011
references.citation: Blood. 2008 Jun 1;111(11):5390-9
references.pmid: 18349318
references.citation: Blood. 2008 Nov 1;112(9):3878-88
references.pmid: 18694996
references.citation: High Alt Med Biol. 2002 Summer;3(2):167-76
references.pmid: 12162861
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1583-8
references.pmid: 11171994
references.citation: Blood. 2006 Sep 1;108(5):1551-4
references.pmid: 16684963
references.citation: Blood. 2006 Apr 1;107(7):2662-72
references.pmid: 16332976
references.citation: Dev Cell. 2009 Oct;17(4):527-40
references.pmid: 19853566
references.citation: Exp Hematol. 2009 Feb;37(2):151-8
references.pmid: 19100675
references.citation: Blood. 2010 Dec 9;116(24):5334-46
references.pmid: 20810925
references.citation: Science. 1990 Apr 20;248(4953):378-81
references.pmid: 2326648
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19500-5
references.pmid: 18048346
references.citation: PLoS One. 2011;6(7):e21192
references.pmid: 21760888
references.citation: Blood. 2005 Sep 1;106(5):1857-63
references.pmid: 15899920
references.citation: Development. 2000 Nov;127(22):4949-58
references.pmid: 11044408
references.citation: EMBO J. 2001 Jun 15;20(12):3156-66
references.pmid: 11406592
references.citation: PLoS One. 2011 Apr 20;6(4):e18856
references.pmid: 21533094
references.citation: Curr Opin Cell Biol. 2003 Apr;15(2):221-31
references.pmid: 12648679
references.citation: Cell. 1998 May 29;93(5):841-50
references.pmid: 9630227
references.citation: Blood. 2009 Aug 27;114(9):1820-30
references.pmid: 19571317
references.citation: J Clin Invest. 2006 Mar;116(3):683-94
references.pmid: 16511603
references.citation: Oncogene. 2006 May 11;25(20):2890-900
references.pmid: 16407844
references.citation: Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11608-12
references.pmid: 8524813