The coupling between transforming growth factor-alpha and the epidermal growth factor receptor during rat liver regeneration.

Transcriptional and post-transcriptional regulation of hepatic expression of the epidermal growth factor receptor (EGF-R) and its autocrine ligand, transforming growth factor-alpha (TGF-alpha), were analyzed during liver regeneration. The EGF-R mRNA levels were about twofold induced at 3 h after hepatectomy, caused by transcriptional activation. This was immediately followed by a decrease, reaching a low at half the initial level after 18 h, due to a decreased transcriptional rate. TGF-alpha mRNA expression was detected in normal liver using solution hybridization analysis. Concurrent with the decrease in EGF receptors, an increase of the TGF-alpha mRNA level occurred, starting at 6 h after hepatectomy and peaking at twice the initial TGF-alpha mRNA level after 12-24 h. For TGF-alpha, however, no increase in the rate of gene transcription could be detected. TGF-alpha and EGF competed for binding to the same hepatic receptor in normal as well as in regenerating liver. TGF-alpha bound to a similar number of binding sites as EGF in both control and 18-h posthepatectomy livers, but with 4-5 times lower affinity than EGF. At 18 h posthepatectomy, the number of binding sites was reduced to about 55% for both ligands. When the subcellular distribution of endocytosed 125I-labeled TGF-alpha was compared with that of 125I-labeled EGF, no differences were observed, and furthermore, no changes were observed in the subcellular distribution of 125I-labeled TGF-alpha during liver regeneration. The distinct and coordinate regulation of the two interactors, EGF-R and TGF-alpha, suggests that the EGF-receptor system may be functionally involved in the different phases of the prereplicative growth stimulatory process during liver regeneration.