Dissociation of proto‐oncogene induction from growth response in normal human fibroblasts

Abstract

Proto-oncogenes are cellular homologues of viral oncogenes that are known to be associated with regulation of growth and differentiation. The c-myc and c-fos proto-oncogenes have been extensively studied by using established cell lines but to a lesser extent by using normal cells. Using physiologic growth modulators, we have shown that mitotic stimulation of normal human dermal fibroblasts is associated with induction of c-myc and c-fos, but that growth inhibition of these cells is not necessarily accompanied by their down-regulation. When treated with both serum and interferon-alpha during quiescence, fibroblasts were delayed in their progress into the S-phase of the cell cycle as compared to cells treated with serum alone and displayed substantial growth inhibition as measured by cell number at the end of 1 week. However, this growth inhibition was not preceded by down-regulation or delay in induction of c-myc and c-fos mRNA. The above studies suggest that in normal fibroblasts growth inhibition is not necessarily dependent on down-regulation of transcription of either c-myc or c-fos and that interferon may act to inhibit cell growth either through a post-transcriptional effect on cellular proto-oncogenes necessary for cell proliferation or through induction of other, as yet unrecognized gene(s) associated with growth arrest.

Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair.

“…The cmyc transcripts were observed 30 min after stimulation and increased to maximal levels at 4-6 h and then decreased to basal levels by 24 h after stimulation. These patterns of expression are consistent with previous reports (Paulsson et al, 1987a;Yaar et al, 1990). In contrast, we could not detect a TGF-f stimulation of c-fos transcripts at any of the time points examined.…”

“…TGF-/ is contained in high amounts in platelets (Assoian et al, 1983) and is produced by both activated macrophages and neutrophils (Assoian et al, 1987;Grotendorst et al, 1989), all of which are present at the initiation of the repair response. TGF-3 has been demonstrated to act as a growth stimulatory factor for mesenchymal cells (Childs et al, 1982;Leof et al, 1986;Yaar et al, 1990) and as a growth inhibitor for endothelial or epithelial cells (Tucker et al, 1984;Heimark et al, 1986;Takehara et al, 1987;Coffey et al, 1988). In addition it can effect the rate of extracellular matrix * Corresponding author.…”

The trk family of receptors mediates nerve growth factor and neurotrophin-3 effects in melanocytes.

“…Significant downregulation of NT-3 mRNA in fibroblasts was also detected within hours after mitogenic stimulation, known from previous studies to induce fibroblast growth (77). In vivo, such conditions are present almost exclusively during wound healing, while in steady-state conditions of undamaged skin, fibroblasts rarely proliferate.…”

Chronic Wound Fluid Suppresses Proliferation of Dermal Fibroblasts Through a Ras-Mediated Signaling Pathway

“…Cells were then serum starved in DMEM with 0.1% CS for 72 h to synchronize them into G0. Seventy-two hours serum starvation of NbFb has previously been shown to induce quiescence in at least 90% of the cells (Yaar et al, 1990).…”