Molecular and Cellular Biology, February 2001, p. 854-864, Vol. 21, No. 3
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.3.854-864.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Departments of Molecular Biology1 and Hematology,2 Jichi Medical School, Tochigi 329-0498, Department of Pediatrics, Yamanashi Medical University, Yamanashi 409-3898,3 Department of Pediatrics, Kyoto Prefectural Medical School, Kyoto 606,4 Institute of Molecular and Cellular Bioscience, University of Tokyo, Tokyo 174,5 and Department of Molecular Oncology, Research Institute for Radation Biology and Medicine, Hiroshima University, Hiroshima 734-8553,8 Japan; Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis Tennessee 381056; and Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 021157
Received 17 July 2000/Returned for modification 20 September 2000/Accepted 2 November 2000
Two distinct signaling pathways regulate the survival of
interleukin-3 (IL-3)-dependent hematopoietic progenitors. One
originates from the membrane-proximal portion of the cytoplasmic domain
of the IL-3 receptor (
c chain), which is shared by IL-3 and
granulocyte-macrophage colony-stimulating factor and is involved in the
regulation of Bcl-xL through activation of STAT5. The other
pathway emanates from the distal region of the
c chain and overlaps
with downstream signals from constitutively active Ras proteins.
Although the latter pathway is indispensable for cell survival, its
downstream targets remain largely undefined. Here we show that the
expression of Bim, a member of the BH3-only subfamily of cell death
activators, is downregulated by IL-3 signaling through either of two
major Ras pathways: Raf/mitogen-activated protein kinase and the
phosphatidylinositol 3-kinase/mammalian target of rapamycin.
Akt/phosphokinase B does not appear to play a significant role in this
regulatory cascade. Bim downregulation has important implications for
cell survival, since enforced expression of this death activator at
levels equivalent to those induced by cytokine withdrawal led to
apoptosis even in the presence of IL-3. We conclude that Bim is a
pivotal molecule in cytokine regulation of hematopoietic cell survival.
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