The c-ets-1 proto-oncogene is a new early-response gene differentially regulated by cytokines and growth factors in human fibroblasts

Abstract

In various invasive human tumors, c-ets-1 mRNA was found to be selectively expressed in stromal fibroblasts. We have now investigated the possibility that soluble factors could regulate c-ets-1 expression in cultured human fibroblasts. We show that both conditioned media from tumor cell lines and a number of characterized cytokines and growth factors were able to induce c-ets-1 expression. TNF alpha and IL-1 alpha were the most potent c-ets-1 stimulators, inducing rapid (within 1 h) and long-lasting (19 h) increases of c-ets-1 mRNA and protein expression. In contrast, bFGF, EGF, and PDGF were mainly delayed stimulators, with maximal stimulation being detected by 19 h. In addition, these growth factors potentiated the rapid induction of c-ets-1 by TNF alpha. While all these factors were able to stimulate c-ets-1 expression, TGF beta was found to be ineffective. Using inhibitors of transcription and translation, we also found that increase of c-ets-1 mRNA by TNF alpha resulted from new transcription rather than from stabilization and did not require new protein synthesis. These results demonstrated that c-ets-1 is a new nuclear target for several factors and behaves as an early-response gene for TNF alpha.