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.
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3 August 1998
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August 03 1998
Transcription Factor SCL Is Required for c-kit Expression and c-Kit Function in Hemopoietic Cells
Gorazd Krosl,
Gorazd Krosl
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
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Gang He,
Gang He
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
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Martin Lefrancois,
Martin Lefrancois
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
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Frédéric Charron,
Frédéric Charron
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
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Paul-Henri Roméo,
Paul-Henri Roméo
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
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Paul Jolicoeur,
Paul Jolicoeur
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
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Ilan R. Kirsch,
Ilan R. Kirsch
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
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Mona Nemer,
Mona Nemer
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
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Trang Hoang
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
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Gorazd Krosl
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
Gang He
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
Martin Lefrancois
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
Frédéric Charron
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
Paul-Henri Roméo
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
Paul Jolicoeur
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
Ilan R. Kirsch
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
Mona Nemer
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
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
Address correspondence to Trang Hoang, Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, Quebec H2W 1R7, Canada. Phone: 514-987-5588; Fax: 514-987-5585; E-mail: [email protected]
Received:
January 28 1998
Revision Received:
April 16 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 188 (3): 439–450.
Article history
Received:
January 28 1998
Revision Received:
April 16 1998
Citation
Gorazd Krosl, Gang He, Martin Lefrancois, Frédéric Charron, Paul-Henri Roméo, Paul Jolicoeur, Ilan R. Kirsch, Mona Nemer, Trang Hoang; Transcription Factor SCL Is Required for c-kit Expression and c-Kit Function in Hemopoietic Cells . J Exp Med 3 August 1998; 188 (3): 439–450. doi: https://doi.org/10.1084/jem.188.3.439
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