Platelet-derived growth factor (PDGF) is an important regulatory molecule known to play a crucial role in development, inflammation, wound healing, atherosclerosis, fibrosis, and cancer. PDGF affects cell proliferation, chemotaxis, cell survival, malignant transformation and apoptosis. The diversity of cellular responses to PDGF may be regulated by coordination of different signaling pathways depending on the genetic background of the target cells and the extracellular milieu. We have recently shown that PDGF induces apoptosis in growth-arrested normal rat kidney fibroblast (NRK) cells. Insulin, a progression factor, rescues PDGF-induced apoptosis in these cells, suggesting the importance of the cell cycle block in this process. Bcl-2, a death suppressing gene, does not protect against this effect of PDGF, suggesting that the PDGF-induced apoptotic pathway is different from other bcl-2 inhibitable apoptotic pathways. These studies suggest a novel role for PDGF in the regulation of programmed cell death. However, the specific mechanisms and signaling pathways involved in PDGF-induced apoptosis are unknown. The long-term objective of this proposal is to unveil the mechanism/s by which PDGF regulates cell growth and death in normal and pathological processes. PDGF induced expression of many cell cycle regulatory genes including p21WAF1/CIP1 and c-myc. p21WAF1/CIP1 is a downstream mediator of p53-induced G1 arrest and possibly apoptosis. Interestingly, PDGF has been shown to induce p21WAF1/CIP1 in fibroblasts lacking p53. In addition, transfection of c-myc causes apoptosis in growth-arrested rat fibroblasts. Our preliminary data show that whereas c-myc is transiently induced during mitogenesis in response to PDGF, c-myc induction is sustained during PDGF-induced apoptosis. These data suggest that c-myc and p21WAF1/CIP1 may be important determinants for the apoptotic response to PDGF. To define the role of c-myc and p21WAF1/CIP1 and the signal transduction pathway involved in PDGF-induced apoptosis, we will: 1. Investigate the role of c-myc in PDGF-induced apoptosis by downregulating c-myc expression or function in NRK cells. 2. Determine whether PDGF-induction of p21WAF1/CIP1 expression causes inhibition of cyclin-dependent kinase activity leading to cell cycle arrest and/or apoptosis. 3. Determine the involvement of p53 in PDGF-induced apoptosis using fibroblast cells lacking p53 or by transfecting mutant p53 into NRK cells. 4. Investigate PDGF alpha- and beta-receptor-mediated signal transduction pathway/s leading to cell death by modulating receptor expression, by mutational analysis of PDGF alpha-receptor, and by measuring activity of the PDGF-regulated signaling molecules: ras, raf and MAPK. The proposed studies will provide fundamental information on the regulation of PDGF-induced apoptosis and will contribute to the understanding of the role of PDGF inflammation, atherosclerosis, and potentially the treatment of cancer by cytostatic drugs and radiation.
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