Constitutive over-expression of transforming growth factor-alpha in rat liver epithelial cells leads to increased cell cycling without transformation.

Over-expression of transforming growth factor-alpha (TGF-alpha) is consistently seen in spontaneous transformants of rat liver derived epithelial cells (RLE phi 13) and has been implicated in the transformation of other cultured cells. We have constitutively over-expressed TGF-alpha in RLE phi 13 cells, which are known to express epidermal growth factor receptors, to determine if TGF-alpha over-expression plays a role in transformation or differentiation, or both, of these cells. Early passage RLE phi 13 cells were infected with a replication-defective murine retrovirus that expresses both the full length coding sequence for human TGF-alpha and the neomycin-resistance gene. Integration of the transcriptionally active provirus and expression of TGF-alpha mRNA were confirmed. Neither morphologic transformation nor molecular evidence for differentiation was noted in TGF-alpha-producing clones. However, these clones did exhibit an accelerated growth rate, increased expression of several cell cycle related genes including mitotic cyclic B1, proliferating cell nuclear antigen, c-myc, and p53 as well as increased expression of the preneoplastic marker enzyme, glutathione-S-transferase. This suggests that over-expression of TGF-alpha results in increased cell cycling, and that subsequent events must be necessary for cellular transformation or differentiation or both.