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Mol Cell Biol, July 1998, p. 3851-3861, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Differential Utilization of Ras Signaling Pathways by Macrophage Colony-Stimulating Factor (CSF) and Granulocyte-Macrophage CSF Receptors during Macrophage Differentiation

Fabien Guidez,dagger Andrew C. Li, Andrew Horvai, John S. Welch, and Christopher K. Glass*

Divisions of Endocrinology and Metabolism and Cellular and Molecular Medicine, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0651

Received 13 October 1997/Returned for modification 26 November 1997/Accepted 27 March 1998

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) independently stimulate the proliferation and differentiation of macrophages from bone marrow progenitor cells. Although the GM-CSF and M-CSF receptors are unrelated, both couple to Ras-dependent signal transduction pathways, suggesting that these pathways might account for common actions of GM-CSF and M-CSF on the expression of macrophage-specific genes. To test this hypothesis, we have investigated the mechanisms by which GM-CSF and M-CSF regulate the expression of the macrophage scavenger receptor A (SR-A) gene. We demonstrate that induction of the SR-A gene by M-CSF is dependent on AP-1 and cooperating Ets domain transcription factors that bind to sites in an M-CSF-dependent enhancer located 4.1 to 4.5 kb upstream of the transcriptional start site. In contrast, regulation by GM-CSF requires a separate enhancer located 4.5 to 4.8 kb upstream of the transcriptional start site that confers both immediate-early and sustained transcriptional responses. Results of a combination of DNA binding experiments and functional assays suggest that immediate transcriptional responses are mediated by DNA binding proteins that are constitutively bound to the GM-CSF enhancer and are activated by Ras. At 12 to 24 h after GM-CSF treatment, the GM-CSF enhancer becomes further occupied by additional DNA binding proteins that may contribute to sustained transcriptional responses. In concert, these studies indicate that GM-CSF and M-CSF differentially utilize Ras-dependent signal transduction pathways to regulate scavenger receptor gene expression, consistent with the distinct functional properties of M-CSF- and GM-CSF-derived macrophages.

* Corresponding author. Mailing address: Division of Cellular and Molecular Medicine, Department of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0651. Phone: (619) 534-6011. Fax: (619) 534-8549. E-mail: cglass{at}ucsd.edu.

dagger Present address: The Institute of Cancer Research, Royal Cancer Hospital, Chester Beatty Laboratories, London, SW3 6JB, United Kingdom.

Mol Cell Biol, July 1998, p. 3851-3861, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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