Transforming growth factor-beta increases transcription of the genes encoding the epidermal growth factor receptor and fibronectin in normal rat kidney fibroblasts.

Abstract

Transforming growth factor-beta (TGF-beta) is a potent modulator of cell growth in many systems. In normal rat kidney (NRK) fibroblasts, TGF-beta synergizes with epidermal growth factor (EGF) to stimulate growth in soft agar, a characteristic of the transformed phenotype. Many biochemical effects of TGF-beta occur at the cell surface. Increased binding of EGF and synthesis of extracellular matrix components such as fibronectin and collagen are primary responses of NRK cells to TGF-beta. Although specific membrane receptors for TGF-beta have been identified, the mechanism of action of this factor is not well understood. Here we demonstrate that TGF-beta enhances the expression of the EGF receptor in NRK cells through an increase in the level of EGF receptor gene transcripts. Analysis of nuclear run-off transcription levels and mRNA half-lives indicate that the elevation in EGF-receptor mRNA results from an increase in the rate of transcription. Dose-response and kinetic studies suggest that the EGF receptor response to TGF-beta is biphasic, possibly resulting from the action of multiple TGF-beta receptors. TGF-beta also elevates the levels of fibronectin and tubulin transcripts in NRK cells; however, the mechanism differs for each gene. The increase in fibronectin mRNA in response to TGF-beta results from an increased rate of gene transcription. Tubulin mRNA levels, in contrast, appear to be post-transcriptionally regulated. These results implicate TGF-beta as a transcriptional activator of the genes for both the EGF receptor and fibronectin and suggest the two genes may be regulated through a common pathway in this cell type.