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Hepatic proliferation inhibitor

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Although a long held tenet of biology has been that endogenous inhibitors can modulate cell proliferation, little progress was made in purifying any such inhibitor. This was largely due to the rarity of non-malignant cell cultures in which regulation of cell division was still operative, and to problems in separating cytotoxic and cytostatic effects in the complex biological extracts which were being studied. During the last decade, hepatic proliferation inhibitors of varying degrees of purity have been isolated using regenerating rat liver or hepatoma cell cultures as test systems. In these early studies, a number of inhibitors with differing molecular weights, physicochemical properties and biological responses were purified from liver cytosol and/or serum. Some of them could inhibit DNA synthesis or mitosis and thus were considered to be G1 or G2 inhibitors. However, experiments which could give precise answers about mechanisms of action could not be done until an inhibitor purified to homogeneity was available.

Using well-characterized rat liver diploid epithelial cell cultures, which maintain a number of liver properties and which do not possess any transformation markers or malignant properties, we recently purified an hepatic proliferation inhibitor to a homogenous protein. It has a molecular weight of 26 000 daltons and an isoelectric point of 4.65. It specifically inhibits cell division and DNA synthesis in a number of non-malignant rat liver epithelial cell types, and has no effect on transformed liver cells, or hepatoma cells, in culture. Its effect is not mediated through destruction or sequestration of essential nutrients or calcium ions. Nor have preliminary experiments shown the hepatic proliferation inhibitor to interfere with the binding of epidermal growth factor to its receptors. The majority of the cells treated with the inhibitor are blocked in the G1 phase. Further experiments to study its mechanism of action and the inter-relationship, if any, between the cell cycle block induced by serum or nutrient deprivation, and the inhibitor-induced cycle block are in progress.

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References

  1. Allen, J. C., 1978. Nature 276: 669.

    Google Scholar 

  2. Allen, T. D. and Iype, P. T., 1979. J. Cancer Res. Clin. Oncol. 95: 225–232.

    Google Scholar 

  3. Allen, T. D., Iype, P. T. and Murphy, M. J., 1976. In Vitro 12: 837–844.

    Google Scholar 

  4. Antoniades, H. N. and Owen, A. J., 1982. Ann. Rev. Med. 33: 445–463.

    Google Scholar 

  5. Aujard, C., Chany, E. & Frayssinet, C., 1973. Expt. Cell Res. 78: 476–478.

    Google Scholar 

  6. Baldwin, R. W. and Barker, C. R., 1967. Br. J. Cancer 21: 793–800.

    Google Scholar 

  7. Barbason, H., Fridman-Manduzio, A., Lelievre, P. and Betz, E. H., 1977. Eur. J. Cancer 13: 13–18.

    Google Scholar 

  8. Barbason, H. and Betz, E. H., 1980. Eur. J. Cancer 17: 149–154.

    Google Scholar 

  9. Barra, R., Parsons, J., Koch, M. R. and Lea, M. A., 1979. Cancer Res. 39: 1655–1660.

    Google Scholar 

  10. Berman, A., Ellouz, R., Lenfant, M. and Garcia-Giralt, E., 1975. C.R. Acad. Sci. Paris 281: 187–190.

    Google Scholar 

  11. Bowen-Pope, D. F., Vidair, C., Sanui, H. and Rubin, A. H., 1979. Proc. Natl. Acad. Sci. U.S.A. 76: 1308–1312.

    Google Scholar 

  12. Brodsky, W. Y. and Uryvaeva, I. V., 1977. Int. Rev. Cytol. 50: 275–332.

    Google Scholar 

  13. Bruscalupi, G., Curatola, G., Lenaz, G., Leoni, S., Mangiantini, M. T., Mazzanti, L., Spagnuolo, S. and Trentalanse, A., 1980. Biochim. Biophys. Acta 597: 263–273.

    Google Scholar 

  14. Bucher, N. L. R., 1963. Int. Rev. Cytol. 15: 245–300.

    Google Scholar 

  15. Bullough, W. S., 1975. Biol. Rev. 50: 99–127.

    Google Scholar 

  16. Campisi, J., Medrano, E. E., Morreo, G. and Pardee, A. B., 1982. Proc. Natl. Acad. Sci. U.S.A. 79: 436–440.

    Google Scholar 

  17. Cannella, N. K., 1977. Life Sci. 20: 155–158.

    Google Scholar 

  18. Cook, R. T., Roetman, K. J. and Steinmetz, G., 1982. Cell Biol. Intl. Rep. b: 49–56.

    Google Scholar 

  19. DePaermentier, F., Barbason, H. and Bassleer, R., 1979. Biologic Cellulaire 34: 205–211.

    Google Scholar 

  20. Deschamps, Y. and Verly, W. G., 1975. Biomedicine 22: 195–208.

    Google Scholar 

  21. Freed, J. J. and Sorof, S., 1967. Wistar Symposium Monograph No. 7, pp. 15–24.

  22. Gospodarowicz, D. and Fujii, D. K., 1981. Cellular Responses to Molecular Modulators (Mozes, L. W., et al., eds.), pp. 113–135, Academic Press, New York.

  23. Hatase, O., Fugii, T., Kuramitsu, M., Itano, T., Takahashi, F., Murakami, T. and Nisida, I, 1979. Acta Med. Okayama 33: 73–80.

    Google Scholar 

  24. Harrington, W. N. and Godman, G. C., 1980. Proc. Natl. Acad. Sci. U.S.A. 77: 423–427.

    Google Scholar 

  25. Herring, A. S., Raychaudhuri, R., Kelley, S. P. and Iype, P. T., 1983. In Vitro 19: 576–588.

    Google Scholar 

  26. Higgins, G. M. and Anderson, R. M., 1931. Arch. Pathol. 12:182–202.

    Google Scholar 

  27. Holley, R. W., 1967. Biochim. Biophys. Acta 145: 523–525.

    Google Scholar 

  28. Holley, R. W., 1975. Nature 258: 487–490.

    Google Scholar 

  29. Holley, R. W., Armour, R. and Baldwin, J. H., 1978. Proc. Natl. Acad. Sci. U.S.A. 75: 339–341.

    Google Scholar 

  30. Inaba, K., Doi, A. and Nisida, L, 1977. Cell Struct. Funct. 2: 155–158.

    Google Scholar 

  31. Iversen, O. H., 1981. Handbook of Experimental Pharmacology (Baserga, R., ed.), Vol. 57, pp. 491–550, Springer, New York.

  32. Iype, P. T., 1971. J. Cell Physiol. 78: 281–288.

    Google Scholar 

  33. Iype, P. T., 1980. Cell Movement and Neoplasia (De Brabander M. et al., eds.), pp. 79–85, Pergamon Press, Oxford and New York.

  34. Type, P. T. and Allen, T. D., 1979. Cancer Lett. 6: 27–32.

    Google Scholar 

  35. Iype, P. T., Allen, T. D. and Pillinger, D. J., 1975. Gene Expression and Carcinogenesis in Cultured Liver (Greschenson, L. E. and Thompson, E. B., eds.), pp. 425–440, Academic Press, New York.

  36. Iype, P. T., Baldwin, R. W. and Glaves, D., 1972. Br. J. Cancer 26: 6–9.

    Google Scholar 

  37. Iype, P. T., Currens, M.J. Herring, A., Kelley, S. P., McMahon, J. B., Ray-Chaudhuri, R. and Malan-Shibley, L., 1982. Proc. Am. Assoc. Cancer Res. 23: 74.

    Google Scholar 

  38. Iype, P. T., Herring, A., Ray-Chadhuri, R. and Kelley, S., 1983. In Vitro Toxicity Testing of Environmental Agents: Current and Future Possibilities (Kolber, A. R. et al., eds.), pp. 337A–354A, Plenum Press, New York.

  39. Iype, P. T., Issaq, H. J. and Shaikh, B., 1982. J. Steroid Biochem. 16: 333–337.

    Google Scholar 

  40. Iype, P. T. and McMahon, J. B., 1981. Cancer Res. 41: 3352–3354.

    Google Scholar 

  41. Iype, P. T. and Pontzer, C. H., 1980. Cancer Res. 40: 4663–4668.

    Google Scholar 

  42. Iype, P. T., Tomaszewski, J. E. and Dipple, A., 1979. Cancer Res. 39: 4925–4929.

    Google Scholar 

  43. Iype, P. T., Turner, S. and Siddiqi, M. S., 1980. Annal. N.Y. Acad. Sci. 349: 312–322.

    Google Scholar 

  44. Ketlinskii, S. A. and Parfenova, E. V., 1981. Bull. Exp. Biol. Med. 92: 971–973.

    Google Scholar 

  45. Kuo, C. Y. and Yoo, T. J., 1977. J. Natl. Cancer Inst. 59: 1691–1695.

    Google Scholar 

  46. Kuramitsu, M., Matsui, H., Tokuda, M. and Hatase, O., 1982. Acta Med. Okayama 36: 1–10.

    Google Scholar 

  47. Lafarge-Frayssinet, C., Mousset, S. and Frayssinet, C., 1981. Biomedicine 34: 99–102.

    Google Scholar 

  48. Lavigne, J., Lalanne, M., Thompson, J. P. and Simard, A., 1977. Rev. Can. Biol. 36: 27–36.

    Google Scholar 

  49. Lenfant, M., Kren-Proschek, L., Verly, W. G. and Dugas, H., 1973. Can. J. Biochem. 51: 654–665.

    Google Scholar 

  50. Liberman, I. and Ove, P., 1960. Biochim. Biophys. Acta 38: 153.

    Google Scholar 

  51. Lipkin, G., Rosenberg, M. and Knecht, M. E., 1976. Biochem. Pharmacol. 25: 1333–1337.

    Google Scholar 

  52. Loginov, A. S., Speranskii, M. D., Aruin, L. I., Matyushina, E. D. and Magnitskii, G. S., 1976. Bull. Exp. Biol. Med. 82: 1482–1484.

    Google Scholar 

  53. Lozzio, S. B., Lozzio, D. B., Bamberger, E. G. and Lair, S. V., 1975. Int. Rev. Cytol. 42: 1–47.

    Google Scholar 

  54. Malan-Shibley, L. and Iype, P. T., 1981. Exptl. Cell Res. 131: 363–371.

    Google Scholar 

  55. McMahon, J. B., Farrelly, J. G. and Iype, P. T., 1982. Proc. Natl. Acad. Sci. U.S.A. 79: 456–460.

    Google Scholar 

  56. McMahon, J. B. and Iype, P. T., 1980. Cancer Res. 40: 1249–1254, 1980.

    Google Scholar 

  57. McMahon, J. B. and Iype, P. T., 1982. J. Liq. Chromatog. 5: 751–756.

    Google Scholar 

  58. McMahon, J. B., Kelleher, P. C. and Smith, C. J., 1977. Biochem. Biophys. Res. Commun. 76: 1144–1150.

    Google Scholar 

  59. Menzies, R. A. and Kerrigan, J. M., 1974. Exptl. Cell Res. 86: 430–433.

    Google Scholar 

  60. Menyhart, J., Marcsek, Z. and Grof, J., 1981. Acta Physiol. Acad. Sci. Hungaricae 58: 119–129.

    Google Scholar 

  61. Meyers, D. J., Yancey, S. B. and Revel, J.-P., 1981. J. Cell Biol. 91: 505–523.

    Google Scholar 

  62. Miyamoto, M. and Terayama, H., 1971. Biochim. Biophys. Acta 228: 324–330.

    Google Scholar 

  63. Molimard, R., Pietu, G., Chany, E., Trincal, G. and Frayssinet, C., 1975. Biomedicine 23: 434–437.

    Google Scholar 

  64. Moses, H. L., Proper, J. A., Volkenant, M. E. and Swartzendruber, D. E., 1980. J. Cell. Physiol. 102: 367–378.

    Google Scholar 

  65. Murray, A. B., Strecker, W. and Silz, S., 1981. J. Cell Sci. 50: 433–448.

    Google Scholar 

  66. Nadal, C., 1973. Cell Tiss. Kinet. 6: 437–446.

    Google Scholar 

  67. Nadal, C., 1975. Virchows Arch. B. Cell Path. 18: 273–280.

    Google Scholar 

  68. Nadal, C., 1979. Arch. Toxicol Suppl. 2: 131–142.

    Google Scholar 

  69. Nadal, C. and Boffa, G. A., 1975. Cell Tiss. Kinet. 8: 297–305.

    Google Scholar 

  70. Nadal, C. and Le Rumeur, E., 1981. Cell Tiss. Kinet. 14: 331–335.

    Google Scholar 

  71. Nadal, C., LeRumeur, E. and Boffa, G. A., 1981. Cell Tiss. Kinet. 14: 601–609.

    Google Scholar 

  72. Nadal, C., Lombard, M. N. and Zajdela, F., 1976. Virchows Arch. B. Cell Pathol. 20: 277–285.

    Google Scholar 

  73. Onda, H., 1977. Gann 68: 301–306.

    Google Scholar 

  74. Onda, H., 1979. J. Theor. Biol. 77: 367–377.

    Google Scholar 

  75. Onda, H. and Yoshikawa, J., 1973. Gann 64: 139–149.

    Google Scholar 

  76. Onda, H. and Yoshikawa, J., 1974. Gann 65: 139–144.

    Google Scholar 

  77. Onda, H. and Yoshikawa, J., 1975. Gann 66: 227–235.

    Google Scholar 

  78. Patt, L. M. and Houck, J. C., 1980. FEBS Lett. 120: 163–170.

    Google Scholar 

  79. Pietu, G., Chany, E., Molimard, R. and Frayssinet, C., 1978. Biomedicine 28: 169–175.

    Google Scholar 

  80. Pietu, G., Munsch, N., Mousset, S. and Frayssinet, C., 1979. Cell Tiss. Kinet. 12: 153–160.

    Google Scholar 

  81. Potter, V. R., 1980. Yale J. Biol. Med. 53: 367–384.

    Google Scholar 

  82. Potter, V. R., 1981. Oncodevelopmental Biology and Medicine 2: 243–266.

    Google Scholar 

  83. Potter, V. R., 1981. Carcinogenesis 2: 1375–1379.

    Google Scholar 

  84. RayChaudhuri, R., Kelley, S. P. and Iype, P. T., 1980. Carcinogenesis 1: 779–785.

    Google Scholar 

  85. Rossow, P. W., Riddle, V. G. H. and Pardee, A. B., 1979. Proc. Natl. Acad. Sci. U.S.A. 76: 4446–4450.

    Google Scholar 

  86. Rudland, P. S. and De Asua, L. J., 1979. Biochim. Biophys. Acta 560: 91–133.

    Google Scholar 

  87. Scott, R. E., Florine, D. L., Wille, J. J. Jr. and Yun, K., 1982. Proc. Natl. Acad. Sci. U.S.A. 79: 845–849.

    Google Scholar 

  88. Sekas, G. and Cook, R. T., 1976. Exptl. Cell Res. 102: 422–425.

    Google Scholar 

  89. Sekas, G., Owen, W. G. and Cook, R. T., 1979. Exptl. Cell Res. 122: 47–54.

    Google Scholar 

  90. Siddiqi, M. and Iype, P. T., 1975. Int. J. Cancer 15: 773–780.

    Google Scholar 

  91. Simard, A., Corneille, L., Deschamps, Y. and Verly, W. G., 1974. Proc. Natl. Acad. Sci. U.S.A. 71: 1763–1766.

    Google Scholar 

  92. Sonnenschein, C. and Soto, A. M., 1981. Proc. Natl. Acad. Sci. U.S.A. 78: 3702–3705.

    Google Scholar 

  93. Sporn, M. B. and Todaro, G. J., 1980. New Engl. J. Med. 303: 878–881.

    Google Scholar 

  94. Stoker, M. G. P., 1974. Control of Proliferation in Animal Cells (Clarkson, B. and Baserga, R., eds.), pp. 1009–1013, Cold Spring Harbor.

  95. Stoker, M., 1981. Cellular Responses to Molecular Modulators (Moses, L. W. et al., eds.), pp. 39–48, Academic Press, New York.

  96. Sunkara, P. S., Pargac, M. B., Nishioka, K. and Rao, P. N., 1979. J. Cell Physiol. 98: 451–458.

    Google Scholar 

  97. Sunkara, P. S., Rao, P. N., Nishioka, K. and Brinkley, B. R., 1979. Exptl. Cell Res. 119: 63–68.

    Google Scholar 

  98. Swierenga, S. H. H., Whitfield, J. F. and Karasaki, S., 1978. Proc. Natl. Acad. Sci. U.S.A. 75: 6069–6072.

    Google Scholar 

  99. Thaler, M. M. and Pickart, L. R., 1975. Gene Expression and Carcinogenesis in Cultured Liver (Greschenson, L. E. and Thompson, E. G., eds.), pp. 292–310. Academic Press, New York.

  100. Thomas, G., Martin-Pérez, J., Siegmann, M. and Otto, A. M., 1982. Cell 30: 235–242.

    Google Scholar 

  101. Tulloch, B. R., Lee, S. and Iype, P. T., 1979. Clin. Res. 27: 261a.

  102. Umansky, S. R., 1982. J. Theor. Biol. 97: 591–602.

    Google Scholar 

  103. Verly, W. G., 1976. Chalones (Houck, J. C., ed.), pp. 401–428, North-Holland Publishing Co., Amsterdam.

  104. Verly, W. G., Deschamps, Y., Pushpathadam, J. and Desrosiers, M., 1971. Can. J. Biochem. 49: 1376–1383.

    Google Scholar 

  105. Vinet, B. and Verly, W. G., 1976. Eurp. J. Cancer 12: 211–218.

    Google Scholar 

  106. Wille, J. J. Jr., Maercklein, P. B. and Scott, R. E., 1982. Cancer Res. 42: 5139–5146.

    Google Scholar 

  107. Yamaguchi, N. and Weinstein, I. B., 1975. Proc. Natl. Acad. Sci. U.S.A. 72: 214–218.

    Google Scholar 

  108. Yen, A. and Pardee, A. B., 1978. Exptl. Cell Res. 116: 103–113.

    Google Scholar 

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  1. Basic Research Program, Chemical Carcinogenesis Program, NCI-Frederick Cancer Research Facility, 21701, Frederick, MD, USA

    P. Thomas Iype & James B. McMahon

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  1. P. Thomas Iype
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Thomas Iype, P., McMahon, J.B. Hepatic proliferation inhibitor. Mol Cell Biochem 59, 57–80 (1984). https://doi.org/10.1007/BF00231305

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