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Molecular and Cellular Biology, April 1999, p. 2754-2762, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Two Distinct Interleukin-3-Mediated Signal Pathways, Ras-NFIL3 (E4BP4) and Bcl-xL, Regulate the Survival of Murine Pro-B Lymphocytes

Ryoko Kuribara,1,2 Taisei Kinoshita,3 Atsushi Miyajima,3 Tetsuharu Shinjyo,1 Takao Yoshihara,4 Takeshi Inukai,4 Keiya Ozawa,1,2 A. Thomas Look,4 and Toshiya Inaba1,*

Departments of Molecular Biology1 and Hematology,2 Jichi Medical School, Tochigi 329-0498, and Institute of Molecular and Cellular Bioscience, the University of Tokyo, Tokyo 174,3 Japan, and Department of Experimental Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 381054

Received 15 July 1998/Returned for modification 6 September 1998/Accepted 22 January 1999

Hematopoietic cells require cytokine-initiated signals for survival as well as proliferation. The pathways that transduce these signals, ensuring timely regulation of cell fate genes, remain largely undefined. The NFIL3 (E4BP4) transcription factor, Bcl-xL, and constitutively active mutants of components in Ras signal transduction pathways have been identified as key regulation proteins affecting murine interleukin-3 (IL-3)-dependent cell survival. Here we show that expression of NFIL3 is regulated by oncogenic Ras mutants through both the Raf-mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways. NFIL3 inhibits apoptosis without affecting Bcl-xL expression. By contrast, Bcl-xL levels are regulated through the membrane proximal portion in the cytoplasmic domain of the receptor (beta c chain), which is shared by IL-3 and granulocyte-macrophage colony-stimulating factor. Activation of either pathway alone is insufficient to ensure cell survival, indicating that multiple independent signal transduction pathways mediate the survival of developing B-lymphoid cells.

* Corresponding author. Mailing address: Department of Molecular Biology, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi-machi, Tochigi 329-0498, Japan. Phone: 81-285-58-7402. Fax: 81-285-44-8675. E-mail: tinaba{at}jichi.ac.jp.

Molecular and Cellular Biology, April 1999, p. 2754-2762, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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