ISOFORM-SPECIFIC INDUCTION OF THE LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE BY PLATELET-DERIVED GROWTH-FACTOR

We investigated the effect of recombinant platelet-derived growth fact or (PDGF) isomers on low-density lipoprotein (LDL) receptor gene expre ssion and compared this with two indexes of cell growth response: expr ession 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 w as more effective in inducing the LDL receptor gene and cell growth re sponse compared with the PDGF-AA homodimer. The second messenger pathw ays utilized by PDGF receptors for enhancing LDL receptor gene respons e could, however, be dissociated from those utilized for enhancing c-m yc gene response and were insensitive to inhibitors of tyrosine phosph orylation. 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 recept or gene in the presence of the PDGF-AA isomer. Our results indicate th at the response of the LDL receptor gene to PDGF isoforms reflects cel lular growth response. However, different transduction pathways are ut ilized for PDGF activation of the c-myc and LDL receptor genes in mese nchymal cells.