Myc is an essential negative regulator of platelet-derived growth factor beta receptor expression.
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-betaR) activates numerous signaling pathways and leads to a decrease in receptor expression on the cell surface. PDGF-betaR downregulation is effected at two levels, the immediate internalization of ligand-receptor complexes and the reduction in pdgf-betar mRNA expression. Our studies show that pdgf-betar mRNA suppression is regulated by the c-myc proto-oncogene. Both constitutive and inducible ectopic Myc protein can suppress pdgf-betar mRNA and protein. Suppression of pdgf-betar mRNA in response to Myc is specific, since expression of the related receptor pdgf-alphar is not affected. We further show that Myc suppresses pdgf-betar 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-betar mRNA expression in quiescent fibroblasts following mitogen stimulation. In addition, it is evident that the Myc-mediated repression of pdgf-betar mRNA levels plays an important role in the regulation of basal pdgf-betar expression in proliferating cells. Thus, our studies suggest an essential role for Myc in a negative-feedback loop regulating the expression of the PDGF-betaR.
Oster
S K
SK
Department of Medical Biophysics, Toronto, Ontario, Canada.
Marhin
W W
WW
Asker
C
C
Facchini
L M
LM
Dion
P A
PA
Funa
K
K
Post
M
M
Sedivy
J M
JM
Penn
L Z
LZ
D016475:3T3 Cells; D000818:Animals; D000077214:Becaplermin; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D015536:Down-Regulation; D007700:Kinetics; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D016271:Proto-Oncogene Proteins c-myc; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D012097:Repressor Proteins; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta