HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Published online before print August 1, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: jlb.0403142v1 74/5/923    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Karlsson, R. Articles by Jönsson, J.-I. Search for Related Content PubMed PubMed Citation Articles by Karlsson, R. Articles by Jönsson, J.-I.

(Journal of Leukocyte Biology. 2003;74:923-931.)
© 2003 by Society for Leukocyte Biology

Phosphatidylinositol 3-kinase is essential for kit ligand-mediated survival, whereas interleukin-3 and flt3 ligand induce expression of antiapoptotic Bcl-2 family genes

Richard Karlsson^*, Maria Engström^*, Maria Jönsson^*, Peter Karlberg^*, Cornelis J.H. Pronk^*, Johan Richter and Jan-Ingvar Jönsson^*,1

^* Division of Molecular Medicine, Department of Laboratory Medicine, Lund University, University Hospital MAS, Malmö, and
Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden

¹Correspondence: Department of Laboratory Medicine University Hospital MAS, Entrance 78, 3rd floor SE-205 02, Malmö, Sweden. E-mail: Jan-Ingvar.Jonsson{at}molmed.mas.lu.se

Cytokines such as interleukin 3 (IL-3), kit ligand (KL), and flt3 ligand (FL) promote survival of hematopoietic stem cells and myeloid progenitor cells. In many cell types, members of the Bcl-2 gene family are major regulators of survival, but the mediating mechanisms are not fully understood. Using two myeloid progenitor cell lines, FDCP-mix and FDC-P1, as well as primary mouse bone marrow progenitors, we demonstrate that KL-mediated survival is dependent on the activation of phosphatidylinositol-3 (PI-3) kinase. The inhibitor LY294002 was able to completely abolish survival mediated by KL, whereas IL-3 and FL were only partially affected. Although all three cytokines induced phosphorylation of protein kinase B (PKB), only KL required PI-3 kinase activity to elicit survival in hematopoietic progenitors. In contrast, pretreatment of cells with inhibitors to the MAP kinase pathway did not affect the survival. We next established if IL-3 and FL activated antiapoptotic Bcl-2 and the related genes Bcl-X_L and Mcl-1. By RNA protection assay and Western blot analysis, we show that all three genes are induced by IL-3, whereas FL induces Bcl-2 and to some extent Bcl-X_L. Importantly, KL could not sustain their expression. Moreover, use of inhibitors implied that IL-3 was mainly exerting its effect on Bcl-2 at the level of transcription. The addition of LY294002 did not affect the expression of Bcl-2 and Bcl-X_L, and thus, we conclude that expression of antiapoptotic Bcl-2 family member genes is not dependent on PI-3 kinase activity. Our results indicate that cytokines exert distinct survival effects and that FL and IL-3 are capable of sustaining progenitor survival by up-regulating the expression of Bcl-2 and related genes.

Key Words: Hematopoiesis • Progenitor • Cytokines • Apoptosis • PKB • Bcl-2

This article has been cited by other articles:

				F. Rezzoug, Y. Huang, M. K. Tanner, M. Wysoczynski, C. L. Schanie, P. M. Chilton, M. Z. Ratajczak, I. J. Fugier-Vivier, and S. T. Ildstad TNF-{alpha} Is Critical to Facilitate Hemopoietic Stem Cell Engraftment and Function J. Immunol., January 1, 2008; 180(1): 49 - 57. [Abstract] [Full Text] [PDF]

				J. M. Irish, N. Anensen, R. Hovland, J. Skavland, A.-L. Borresen-Dale, O. Bruserud, G. P. Nolan, and B. T. Gjertsen Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53 Blood, March 15, 2007; 109(6): 2589 - 2596. [Abstract] [Full Text] [PDF]

				K. J. Hutt, E. A. McLaughlin, and M. K. Holland KIT/KIT Ligand in Mammalian Oogenesis and Folliculogenesis: Roles in Rabbit and Murine Ovarian Follicle Activation and Oocyte Growth Biol Reprod, September 1, 2006; 75(3): 421 - 433. [Abstract] [Full Text] [PDF]

				C. Moller, J. Alfredsson, M. Engstrom, H. Wootz, Z. Xiang, J. Lennartsson, J.-I. Jonsson, and G. Nilsson Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim Blood, August 15, 2005; 106(4): 1330 - 1336. [Abstract] [Full Text] [PDF]

				S. Basu and H. E. Broxmeyer Transforming growth factor-{beta}1 modulates responses of CD34+ cord blood cells to stromal cell-derived factor-1/CXCL12 Blood, July 15, 2005; 106(2): 485 - 493. [Abstract] [Full Text] [PDF]

				P. Kempna, E. Reiter, M. Arock, A. Azzi, and J.-M. Zingg Inhibition of HMC-1 Mast Cell Proliferation by Vitamin E: INVOLVEMENT OF THE PROTEIN KINASE B PATHWAY J. Biol. Chem., December 3, 2004; 279(49): 50700 - 50709. [Abstract] [Full Text] [PDF]

				N. J. Lacayo, S. Meshinchi, P. Kinnunen, R. Yu, Y. Wang, C. M. Stuber, L. Douglas, R. Wahab, D. L. Becton, H. Weinstein, et al. Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes Blood, November 1, 2004; 104(9): 2646 - 2654. [Abstract] [Full Text] [PDF]