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

Abstract

ABSTRACT 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 β receptor (PDGF-βR) activates numerous signaling pathways and leads to a decrease in receptor expression on the cell surface. PDGF-βR downregulation is effected at two levels, the immediate internalization of ligand-receptor complexes and the reduction in pdgf-βr mRNA expression. Our studies show that pdgf-βr mRNA suppression is regulated by the c- myc proto-oncogene. Both constitutive and inducible ectopic Myc protein can suppress pdgf-βr mRNA and protein. Suppression of pdgf-βr mRNA in response to Myc is specific, since expression of the related receptor pdgf-αr is not affected. We further show that Myc suppresses pdgf-βr 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-βr mRNA expression in quiescent fibroblasts following mitogen stimulation. In addition, it is evident that the Myc-mediated repression of pdgf-βr mRNA levels plays an important role in the regulation of basal pdgf-βr expression in proliferating cells. Thus, our studies suggest an essential role for Myc in a negative-feedback loop regulating the expression of the PDGF-βR.