A new cell line (Hep 3B-TR), which is resistant to growth-inhibition by transforming growth factor beta 1 (TGF-beta 1) up to 10 ng/ml (400 pM), was isolated from parental Hep 3B human hepatoma cells, which are sensitive to growth-inhibition by TGF-beta 1. In the presence of TGF-beta 1 (1 to 10 ng/ml), the growth of the parental cell line (Hep 3B-TS) was inhibited by more than 95%. Under the same conditions, the growth rate of the resistant clone (Hep 3B-TR) however, was identical in the presence or absence of TGF-beta 1 and was almost the same as that of the Hep 3B-TS cells in the absence of TGF-beta 1. Affinity crosslinking with 5 pM 125I-labeled TGF-beta 1 showed that the TGF-beta 1 receptors type I (TGF-beta RI) and type II (TGF-beta RII) were not present on the cell surface of the Hep 3B-TR cells, whereas they were present on the sensitive HEP 3B-TS cells. Hep 3B-TS cells had detectable TGF-beta RII mRNA, which was not found in Hep 3B-TR cells. RNA analysis showed different effects on the expression of TGF-beta 1, c-fos, c-myc, and protein disulfide isomerase (PDI) genes in the two cell lines in response to TGF-beta 1 protein. Addition of TGF-beta 1 (1 ng/ml) strongly increased the expression of TGF-beta 1 mRNA in Hep 3B-TS cells, but not in Hep 3B-TR cells.(ABSTRACT TRUNCATED AT 250 WORDS)