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Molecular and Cellular Biology, September 2000, p. 6768-6778, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Myc Is an Essential Negative Regulator of Platelet-Derived Growth Factor Beta Receptor Expression

Sara K. Oster,1,2 Wilson W. Marhin,2,3 Charlotte Asker,2,dagger Linda M. Facchini,2,3,Dagger Patrick A. Dion,2,§ Keiko Funa,4 Martin Post,5 John M. Sedivy,6 and Linda Z. Penn1,2,3,*

Departments of Medical Biophysics1 and Molecular and Medical Genetics,2 University of Toronto, and Ontario Cancer Institute,3 Toronto, Ontario, Canada M5G 2M9; Department of Pediatrics, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada M5G 1X85; Institute of Anatomy and Cell Biology, Göteborg University, SE-405 30 Gothenburg, Sweden4; and Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island 029126

Received 9 May 2000/Accepted 19 June 2000

Platelet-derived growth factor BB (PDGF BB) is a potent mitogen for fibroblasts as well as many other cell types. Interaction of PDGF BB with the PDGF beta  receptor (PDGF-beta R) activates numerous signaling pathways and leads to a decrease in receptor expression on the cell surface. PDGF-beta R downregulation is effected at two levels, the immediate internalization of ligand-receptor complexes and the reduction in pdgf-beta r mRNA expression. Our studies show that pdgf-beta r mRNA suppression is regulated by the c-myc proto-oncogene. Both constitutive and inducible ectopic Myc protein can suppress pdgf-beta r mRNA and protein. Suppression of pdgf-beta r mRNA in response to Myc is specific, since expression of the related receptor pdgf-alpha r is not affected. We further show that Myc suppresses pdgf-beta r mRNA expression by a mechanism which is distinguishable from Myc autosuppression. Analysis of c-Myc-null fibroblasts demonstrates that Myc is required for the repression of pdgf-beta r mRNA expression in quiescent fibroblasts following mitogen stimulation. In addition, it is evident that the Myc-mediated repression of pdgf-beta r mRNA levels plays an important role in the regulation of basal pdgf-beta r expression in proliferating cells. Thus, our studies suggest an essential role for Myc in a negative-feedback loop regulating the expression of the PDGF-beta R.

* Corresponding author. Mailing address: Division of Cellular and Molecular Biology, Department of Medical Biophysics, 610 University Ave., Toronto, Ontario, Canada M5G 2M9. Phone: (416) 946-2276. Fax: (416) 946-2065. E-mail: lpenn{at}oci.utoronto.ca.

dagger Present address: Rodiumhemmet, Karolinska Sjukhuset, S-171 76 Stockholm, Sweden.

Dagger Present address: Department of Microbiology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada M5G 1X8.

§ Present address: The Montreal General Hospital Institute, Centre for Research in Neurosciences, Montreal, Quebec, Canada H3G 1A4.

Molecular and Cellular Biology, September 2000, p. 6768-6778, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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