Summary
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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References
Derynck, R.J., J. Cell. Biochem., 32 (1986) 1.
Derynck, R.J., Cell, 54 (1988) 593.
Massague, J., J. Biol. Chem., 265 (1990) 21393.
DeLarco, J.E. and Todaro, G.J., Proc. Natl. Acad. Sci. USA, 75 (1978) 4001.
Rappolee, D.A., Mark, D., Banda, M.J. and Werb, Z., Science, 241 (1988) 708.
Elder, J.T., Fisher, G.J., Lindquist, P.B., Bennett, G.L., Pittelkow, M.R., Coffey Jr., R.J., Ellinsworth, L., Derynck, R.J. and Voorhees, J.J., Science, 243 (1989) 811.
Mueller, S.G., Paterson, A.J., and Kudlow, J.E., Mol. Cell. Biol., 10 (1990) 4596.
Lee, D.C., Rose, T.M., Webb, N.R. and Todaro, G.J., Nature, 313 (1985) 489.
Ignotz, R.A., Kelly, B., Davis, R.J. and Massague, J., Proc. Natl. Acad. Sci. USA, 83 (1986) 6307.
Teixido, J., Gilmore, R., Lee, D.C. and Massague, J., Nature, 326 (1987) 883.
Lee, D.C. and Han, K.M., In Sporn, M.B. and Roberts, A.B. (Eds.) Peptide Growth Factors and Their Receptors, Springer, New York, NY, 1991, pp. 611–654.
Derynck, R.J., Roberts, A.B., Winkler, M.E., Chen, E.Y. and Goeddel, D.V., Cell, 38 (1984) 287.
Lee, D.C., Rose, T.M., Webb, N.R. and Todaro, G.J., Nature, 313 (1985) 489.
Bringman, T.S., Lindquist, P.B. and Derynck, R., Cell, 48 (1987) 429.
Gentry, L.E., Twardzik, D.R., Lim, G.J., Ranchalis, J.E. and Lee, D.C., Mol. Cell. Biol., 7 (1987) 1585.
Teixido, J., Gilmore, R., Lee, D.C. and Massague, J., Nature, 326 (1987) 883.
Massague, J. and Pandiella, A., Annu. Rev. Biochem., 62 (1993) 515.
Harris, R.B., Arch. Biochem. Biophys., 275 (1989) 313.
Harris, R.B., You, J.L., Milton, S.C.F., DeLisle Milton, R.C., Rangaraju, N.S. and Baker, C.P., In Hedin, P.A., Menn, J.J. and Hollingworth, R.M. (Eds.) Natural and Derived Pest Management Agents, American Chemical Society, Washington, DC, 1994, pp. 230–249.
Brown, S.B., Krause, D. and Ellem, K.A.O., J. Cell. Biochem., 51 (1993) 102.
Cappelluti, E. and Harris, R.B., Biochemistry, 32 (1993) 551.
Wong, S.T., Winchell, L.F., McCune, B.K., Earp, H.S., Teixido, J. and Massague, J., Cell, 56 (1989) 495.
Brachmann, R., Lindquist, P.B., Nagashima, M., Kohr, W., Lipari, T., Napier, M. and Derynck, R., Cell, 56 (1989) 691.
Anklesaria, P., Teixido, J., Laiho, M., Pierce, J., Greenberger, J. and Massague, J., Proc. Natl. Acad. Sci. USA, 87 (1990) 3289.
Teixido, J., Wong, S.T., Lee, D.C. and Massague, J., J. Biol. Chem., 265 (1990) 6410.
Pandiella, A. and Massague, J., Proc. Natl. Acad. Sci. USA, 88 (1991) 1726.
Strom, S.C., Faust, J.B., Cappelluti, E., Harris, R.B. and Lalwani, N.D., Dig. Dis. Sci., 36 (1991) 642.
Levine, A.E., Int. J. Cancer, 58 (1994) 129.
Gearing, A.J.H., Beckett, P., Christodoulou, M., Churchill, M., Clement, J., Davidson, A.H., Drummon, A.H., Galloway, W.A., Gilbert, R., Gordon, J.L., Leber, T.M., Mangan, M., Miller, K., Nayee, P., Owen, K., Patel, S., Thomas, W., Wells, G., Wood, L.M. and Woolley, K., Nature, 370 (1994) 555.
McGeehan, G.M., Becherer, J.D., Bast Jr., R.C., Boyer, C.M., Champion, B., Connolly, K.M., Conway, J.G., Furdon, Pl., Karp, S., Kidao, S., McElroy, A.B., Nichols, J., Pryzwansky, K.M., Schoenen, F., Sekut, L., Truesdal, A., Verghese, M., Warner, J. and Ways, J.P., Nature, 370 (1994) 558.
Doherty, J.B., Ashe, B.M., Argenbright, L.W., Barker, P.L., Bonney, R.J., Chandler, G.O., Dahlgren, M.E., Dorn, C.P., Finke, P.E., Firestone, R.A., Fletcher, D., Hagmann, W.K., Mumford, R.A., O'Grady, L., Maycock, R.A., Pisano, J.M., Shah, S.K., Thompson, K.R. and Zimmerman, M., Nature, 322 (1986) 192.
Davies, P., Ashe, B.M., Bonney, R.J., Dorn, C., Finke, P., Fletcher, D., Hanlon, W.A., Humes, J.L., Maycock, A., Mumford, R.A., Navia, M.A., Opas, E.E., Pacholok, S., Shah, S., Zimmerman, M. and Doherty, J.B., Ann. New York Acad. Sci., 624 (1990) 219.
Schmidt-Ullrich, R.K., Valerie, K., Chan, W., Wazer, D.E. and Lin, P.S., Int. J. Radiat. Biol., 61 (1992) 405.
Dickson, R.B., McManawy, M.E. and Lippman, M.E., Science, 232 (1987) 1540.
Bates, S.E., Davidson, N.E., Valverius, E.M., Freter, C., Dickson, R.B., Tam, J.P., Kudlow, J.E., Lippman, M.E. and Salomon, D.S., Mol. Endocrinol., 2 (1988) 543.
Finlay, T.H., Tamir, S., Kadner, S.S., Cruz, M.R., Yavelow, J. and Levitz, M., Endocrinology, 133 (1993) 996.
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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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DOI: https://doi.org/10.1007/BF02172029