Downregulation of Bim, a Proapoptotic Relative of Bcl-2, Is a Pivotal Step in Cytokine-Initiated Survival Signaling in Murine Hematopoietic Progenitors

doi:10.1128/MCB.21.3.854-864.2001

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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.

Downregulation of Bim, a Proapoptotic Relative of Bcl-2, Is a Pivotal Step in Cytokine-Initiated Survival Signaling in Murine Hematopoietic Progenitors

Tetsuharu Shinjyo,¹ Ryoko Kuribara,¹^,² Takeshi Inukai,³ Hajime Hosoi,⁴ Taisei Kinoshita,⁵ Atsushi Miyajima,⁵ Peter J. Houghton,⁶ A. Thomas Look,⁷ Keiya Ozawa,¹^,² and Toshiya Inaba¹^,⁸^,^*

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 originatesfrom the membrane-proximal portion of the cytoplasmic domain ofthe IL-3 receptor ( $beta$ c chain), which is shared by IL-3 and granulocyte-macrophagecolony-stimulating factor and is involved in the regulation ofBcl-x_L through activation of STAT5. The other pathway emanatesfrom the distal region of the $beta$ c chain and overlaps with downstreamsignals from constitutively active Ras proteins. Although thelatter pathway is indispensable for cell survival, its downstreamtargets remain largely undefined. Here we show that the expressionof Bim, a member of the BH3-only subfamily of cell death activators,is downregulated by IL-3 signaling through either of two majorRas pathways: Raf/mitogen-activated protein kinase and the phosphatidylinositol3-kinase/mammalian target of rapamycin. Akt/phosphokinase B doesnot 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 equivalentto those induced by cytokine withdrawal led to apoptosis evenin the presence of IL-3. We conclude that Bim is a pivotal moleculein cytokine regulation of hematopoietic cellsurvival.

^* Corresponding author. Mailing address: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine,Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553,Japan. Phone: 81-82-257-5834. Fax: 81-82-256-7103.

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