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Blood, 15 September 2004, Vol. 104, No. 6, pp. 1679-1687. Prepublished online as a Blood First Edition Paper on May 27, 2004; DOI 10.1182/blood-2004-04-1362. This Article Full Text (PDF) All Versions of this Article: 2004-04-1362v1 104/6/1679    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 Zhang, J. Articles by Lodish, H. F Search for Related Content PubMed PubMed Citation Articles by Zhang, J. Articles by Lodish, H. F Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 9, 2004 Accepted May 11, 2004 Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors Jing Zhang and Harvey F Lodish* Whitehead Institute for Biomedical Research, Cambridge, MA, USA Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA * Corresponding author; email: lodish{at}wi.mit.edu. Oncogenic mutations in ras genes frequently occur in patients with myeloid disorders and in these patients erythropoiesis is often affected. Previously we showed that expression of oncogenic H-ras in purified mouse primary fetal liver erythroid progenitors blocks terminal erythroid differentiation and supports Epo-independent proliferation. As a first step in understanding the underlying molecular mechanisms we examined the signaling pathways downstream of Ras in primary erythroid cells. We found that three major pathways are abnormally activated by oncogenic H-ras: Raf/ERK, PI3-kinase/Akt and RalGEF/RalA. However, only constitutive activation of the MEK/ERK pathway alone could recapitulate all of the effects of oncogenic H-ras expression in blocking erythroid differentiation and inducing Epo-independent proliferation. While expression of a constitutively active Akt kinase (ca.Akt) in erythroid progenitors does not significantly affect erythroid differentiation in the presence of erythropoietin (Epo), coexpression of ca.Akt together with a constitutively active MEK causes prolonged Epo-independent proliferation of erythroid progenitors in addition to a block in differentiation. Moreover, the effects of oncogenic H-ras expression on primary erythroid cells are blocked by the addition of U0126, a specific inhibitor of MEK1/2, allowing normal terminal erythroid proliferation and differentiation. Our data suggest that the interruption of constitutive MEK/ERK signaling is a potential therapeutic strategy to correct impaired erythroid differentiation in patients with myeloid disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Too much ERK, not enough erythrocytes Thomas M. Guadagno Blood 2004 104: 1591-1592. [Full Text] [PDF] This article has been cited by other articles: A. Elorza, B. Hyde, H. K. Mikkola, S. Collins, and O. S. Shirihai UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis J. Biol. Chem., November 7, 2008; 283(45): 30461 - 30470. [Abstract] [Full Text] [PDF] D. M. Gilkes, Y. Pan, D. Coppola, T. Yeatman, G. W. Reuther, and J. Chen Regulation of MDMX Expression by Mitogenic Signaling Mol. Cell. Biol., March 15, 2008; 28(6): 1999 - 2010. [Abstract] [Full Text] [PDF] J. Zhang, Y. Liu, C. Beard, D. A. Tuveson, R. Jaenisch, T. E. Jacks, and H. F. Lodish Expression of oncogenic K-ras from its endogenous promoter leads to a partial block of erythroid differentiation and hyperactivation of cytokine-dependent signaling pathways Blood, June 15, 2007; 109(12): 5238 - 5241. [Abstract] [Full Text] [PDF] J. Shuga, J. Zhang, L. D. Samson, H. F. Lodish, and L. G. Griffith In vitro erythropoiesis from bone marrow-derived progenitors provides a physiological assay for toxic and mutagenic compounds PNAS, May 22, 2007; 104(21): 8737 - 8742. [Abstract] [Full Text] [PDF] B. S. Braun, J. A. Archard, J. A. G. Van Ziffle, D. A. Tuveson, T. E. Jacks, and K. Shannon Somatic activation of a conditional KrasG12D allele causes ineffective erythropoiesis in vivo Blood, September 15, 2006; 108(6): 2041 - 2044. [Abstract] [Full Text] [PDF] C. Rubiolo, D. Piazzolla, K. Meissl, H. Beug, J. C. Huber, A. Kolbus, and M. Baccarini A balance between Raf-1 and Fas expression sets the pace of erythroid differentiation Blood, July 1, 2006; 108(1): 152 - 159. [Abstract] [Full Text] [PDF] N. Omidvar, L. Pearn, A. K. Burnett, and R. L. Darley Ral Is both Necessary and Sufficient for the Inhibition of Myeloid Differentiation Mediated by Ras Mol. Cell. Biol., May 15, 2006; 26(10): 3966 - 3975. [Abstract] [Full Text] [PDF] M. P. Menon, J. Fang, and D. M. Wojchowski Core erythropoietin receptor signals for late erythroblast development Blood, April 1, 2006; 107(7): 2662 - 2672. [Abstract] [Full Text] [PDF] S. Schubbert, K. Lieuw, S. L. Rowe, C. M. Lee, X. Li, M. L. Loh, D. W. Clapp, and K. M. Shannon Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells Blood, July 1, 2005; 106(1): 311 - 317. [Abstract] [Full Text] [PDF]

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