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Proteolytic maturation of transforming growth factor-α

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Transforming growth factor-α (TGF-α) is a mitogenic peptide hormone produced extracellularly, by tumor cells, and by virally and chemically transformed cells in culture. TGF-α is almost certainly derived from its precursor protein (pro-TGF-α) by limited endoproteolysis, but physiologically relevant processing enzyme(s) of the pro-TGF-α protein and the cellular or subcellular compartment in which processing takes place are not known with certainty. We previously detailed [Cappelluti, E. and Harris, R.B., Biochemistry, 32 (1993) 551] the discovery, characterization and purification of novel, elastase-like enzymes (molecular weight 38 000) from oncogenically transformed rat liver epithelial cells or cultural Schwann cells transfected with SV40-large T antigen. The elastase-like enzyme appeared to be specifically induced in the transformed epithelial cells compared with the level of enzyme in the nontransformed parental cells. In the intervening time, other elastase-like serine proteinases have been implicated in processing pro-TGF-α in other human carcinoma cell lines. We now report that the elastase-like enzymes, purified from transformed Schwann or liver epithelial cells, are inhibited in a time- and concentration-dependent fashion with three differently substituted monocyclic β-lactam-based compounds originally developed as specific inhibitors of polymorphonuclear leukocyte elastase, thus further supporting the elastase-like character of the putative pro-TGF-α processing enzymes. We also report the presence of the elastase-like enzyme in two different human malignant mammary cell lines, but even though MCF-7 cells receiving high doses of radiation in vitro show an increased level of expression of TGF-α, the elastase-like enzyme does not appear to be induced in these cells following irradiation.

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Correspondence to Robert B. Harris.

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Cappelluti, E., Harris, R.B. Proteolytic maturation of transforming growth factor-α. Perspectives in Drug Discovery and Design 2, 353–361 (1995). https://doi.org/10.1007/BF02172029

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Key words

  • Breast cancer cells
  • Elastase
  • Enzyme inhibitors
  • Processing enzymes
  • pro-TGF-α
  • Serine proteinase
  • TGF-α