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Gorazd Krosl^*, Gang He^*,¶, Martin Lefrancois^*,¶, Frédéric Charron^*,, Paul-Henri Roméo, Paul Jolicoeur^*,||,¶, Ilan R. Kirsch^**, Mona Nemer^*,,,¶, and Trang Hoang^*,,,¶

From the ^* Clinical Research Institute of Montreal, Montréal, Quebec H2W 1R7, Canada; the Department of Pharmacology, the Department of Biochemistry, the ^|| Department of Microbiology-Immunology, and ^¶ The Program of Molecular Biology, University of Montreal, Montreal, Quebec H3C 3J7, Canada; ^** The National Cancer Institute, Naval Medical Center, Bethesda, Maryland 20892; The Department of Medicine, McGill University, Montreal, Quebec H3A 2A7, Canada; and Institut National de la Santé et de la Recherche Médicale U.91, Hôpital Henri Mondor, 94010 Créteil, France

In normal hemopoietic cells that are dependent on specific growth factors for cell survival, the expression of the basic helix-loop-helix transcription factor SCL/Tal1 correlates with that of c-Kit, the receptor for Steel factor (SF) or stem cell factor. To address the possibility that SCL may function upstream of c-kit, we sought to modulate endogenous SCL function in the CD34⁺ hemopoietic cell line TF-1, which requires SF, granulocyte/macrophage colony–stimulating factor, or interleukin 3 for survival. Ectopic expression of an antisense SCL cDNA (as-SCL) or a dominant negative SCL (dn-SCL) in these cells impaired SCL DNA binding activity, and prevented the suppression of apoptosis by SF only, indicating that SCL is required for c-Kit–dependent cell survival. Consistent with the lack of response to SF, the level of c-kit mRNA and c-Kit protein was significantly and specifically reduced in as-SCL– or dn-SCL– expressing cells. c-kit mRNA, c-kit promoter activity, and the response to SF were rescued by SCL overexpression in the antisense or dn-SCL transfectants. Furthermore, ectopic c-kit expression in as-SCL transfectants is sufficient to restore cell survival in response to SF. Finally, enforced SCL in the pro–B cell line Ba/F3, which is both SCL and c-kit negative is sufficient to induce c-Kit and SF responsiveness. Together, these results indicate that c-kit, a gene that is essential for the survival of primitive hemopoietic cells, is a downstream target of the transcription factor SCL.

Key Words: SCL • TAL1 • c-kit • apoptosis • Steel factor

Abbreviations used: as-SCL, antisense SCL; dn-SCL, dominant negative SCL; GAPDH, rat glyceraldehyde-3-phosphate dehydrogenase; MSCV, murine stem cell virus; SF, Steel factor.

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