AUTO-INDUCTION AND CROSS-INDUCTION WITHIN THE MAMMALIAN EPIDERMAL GROWTH FACTOR-RELATED PEPTIDE FAMILY

Several polypeptide growth factors related to epidermal growth factor (EGF) have been identified recently, including transforming growth fac tor-alpha (TGF-alpha), amphi-regulin (AR), heparin-binding EGF-like gr owth factor (HB-EGF), and betacellulin (BTC). These peptides all bind to the EGF receptor (EGFr). in an effort to understand redundancy with in this peptide family and interactions among these related peptides, we compared the biological activities of EGF, TGF-alpha, AR, and HB-EG F in an EGF-responsive, nontransformed intestinal epithelial line (RIE -1) and also determined the effect of individual EGF-related peptides on the expression of related family members in these cells. TGF-alpha, AR, HB-EGF, and EGF were equipotent in stimulating [H-3]thymidine inc orporation by RIE-1 cells and bound the EGFr with equivalent affinity. Each EGF-related peptide induced the mRNA expression of the remaining family members, including BTC. HB-EGF and AR mRNAs were induced rapid ly (within 30 min) and to a greater extent than TGF-alpha and BTC mRNA s, suggesting heterogeneity in the molecular mechanisms for induction. This same pattern was observed for all EGF-related peptides tested. A similar pattern of mRNA induction was observed in secondary cultures of human keratinocytes and in LIM1215 colon adenocarcinoma cells. Nucl ear run-on analysis showed that induction of AR and HB-EGF is, at leas t in part, regulated at the level of gene transcription. Concurrent tr eatment with HE-EGF and cycloheximide resulted in superinduction of HB -EGF and AR, suggesting that these peptides are immediate early genes in RIE-1 cells. Our results demonstrate an equivalent biological respo nse to EGF-related peptides in RIE-1 cells and further indicate that e xtensive auto-induction and cross-induction occur within the EGF-relat ed peptide family in several EGF-responsive epithelial cell types.