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Blood, 1 June 2008, Vol. 111, No. 11, pp. 5390-5399. Prepublished online as a Blood First Edition Paper on March 18, 2008; DOI 10.1182/blood-2007-10-119743. This Article Full Text (PDF) All Versions of this Article: blood-2007-10-119743v1 111/11/5390    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sathyanarayana, P. Articles by Wojchowski, D. M Search for Related Content PubMed PubMed Citation Articles by Sathyanarayana, P. Articles by Wojchowski, D. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 23, 2007 Accepted March 3, 2008 EPO receptor circuits for primary erythroblast survival Pradeep Sathyanarayana, Arvind Dev, Jing Fang, Estelle Houde, Olga Bogacheva, Oleg Bogachev, Madhu Menon, Sarah Browne, Anamika Pradeep, Christine Emerson, and Don M Wojchowski* Stem & Progenitor Cell Biology Program, Molecular Medicine Division, Maine Medical Center Research Institute, Scarborough, ME, United States * Corresponding author; email: wojchd{at}mmc.org. EPO functions primarily as an erythroblast survival factor, and its anti-apoptotic actions have been proposed to involve predominantly PI3-kinase and BCL-X pathways. Presently, the nature of EPO-regulated survival genes has been interrogated through transcriptome analyses of highly-responsive, primary bone marrow erythroblasts. Two pro-apoptotic 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-HM 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 wild-type EPOR activities. EPOR-H and the wild-type EPOR (but not EPOR-HM) 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 KitposCD71highTer119neg 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 anti-apoptotic effectors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Sathyanarayana, E. Houde, D. Marshall, A. Volk, D. Makropoulos, C. Emerson, A. Pradeep, P. J. Bugelski, and D. M. Wojchowski CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools Blood, May 14, 2009; 113(20): 4955 - 4962. [Abstract] [Full Text] [PDF]

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