Isoform-specific induction of the low-density lipoprotein receptor gene by platelet-derived growth factor.
We investigated the effect of recombinant platelet-derived growth factor (PDGF) isomers on low-density lipoprotein (LDL) receptor gene expression and compared this with two indexes of cell growth response: expression of the immediate early gene c-myc and the rate of DNA synthesis. In human skin fibroblasts and NIH 3T3 cells, the PDGF-BB homodimer was more effective in inducing the LDL receptor gene and cell growth response compared with the PDGF-AA homodimer. The second messenger pathways utilized by PDGF receptors for enhancing LDL receptor gene response could, however, be dissociated from those utilized for enhancing c-myc gene response and were insensitive to inhibitors of tyrosine phosphorylation. Inhibition of tyrosine kinase activity inhibited c-myc gene response to PDGF-BB at 10(-8) M but had little effect on LDL receptor gene response. Such inhibition increased expression of the LDL receptor gene in the presence of the PDGF-AA isomer. Our results indicate that the response of the LDL receptor gene to PDGF isoforms reflects cellular growth response. However, different transduction pathways are utilized for PDGF activation of the c-myc and LDL receptor genes in mesenchymal cells.
Rechtoris
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C
Department of Medicine, Rush Medical College, Chicago, Illinois 60612, USA.
Mazzone
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T
D016475:3T3 Cells; D000818:Animals; D000077214:Becaplermin; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D016259:Genes, myc; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D018110:Receptors, Lipoprotein / Q000235:genetics*; D011994:Recombinant Proteins; D015290:Second Messenger Systems; D012867:Skin / Q000166:cytology; D012879:Skin Physiological Phenomena
D008077:Lipoproteins, LDL; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D018110:Receptors, Lipoprotein; D011994:Recombinant Proteins; C075278:platelet-derived growth factor A; D000077214:Becaplermin