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. 1989 Mar;86(5):1558–1562. doi: 10.1073/pnas.86.5.1558

Transforming growth factor alpha may be a physiological regulator of liver regeneration by means of an autocrine mechanism.

J E Mead 1, N Fausto 1
PMCID: PMC286737  PMID: 2922399

Abstract

We investigated whether transforming growth factor alpha (TGF-alpha) is involved in hepatocyte growth responses both in vivo and in culture. During liver regeneration after partial hepatectomy in rats, TGF-alpha mRNA increased; it reached a maximum (approximately 9-fold higher than normal) at the peak of DNA synthesis. The message and the peptide were localized in hepatocytes and found in higher amounts in hepatocytes obtained from regenerating liver. TGF-alpha caused a 13-fold elevation of DNA synthesis in hepatocytes in primary culture and was slightly more effective than epidermal growth factor. TGF-beta blocked TGF-alpha stimulation when added either simultaneously with TGF-alpha or a day later. TGF-alpha message increased in hepatocytes stimulated to undergo DNA synthesis by TGF-alpha or epidermal growth factor, and the peptide was detected in the culture medium by RIA. In the regenerating liver, the increase in TGF-alpha mRNA during the first day after partial hepatectomy coincided with an increase in epidermal growth factor/TGF-alpha receptor mRNA and a decrease (already reported) in the number of these receptors. We conclude that TGF-alpha may function as a physiological inducer of hepatocyte DNA synthesis during liver regeneration by means of an autocrine mechanism and that its stimulatory effects in this growth process are balanced by the inhibitory action of TGF-beta 1.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bartles J. R., Hubbard A. L. Preservation of hepatocyte plasma membrane domains during cell division in situ in regenerating rat liver. Dev Biol. 1986 Nov;118(1):286–295. doi: 10.1016/0012-1606(86)90095-3. [DOI] [PubMed] [Google Scholar]
  2. Braun L., Mead J. E., Panzica M., Mikumo R., Bell G. I., Fausto N. Transforming growth factor beta mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1539–1543. doi: 10.1073/pnas.85.5.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Carr B. I., Hayashi I., Branum E. L., Moses H. L. Inhibition of DNA synthesis in rat hepatocytes by platelet-derived type beta transforming growth factor. Cancer Res. 1986 May;46(5):2330–2334. [PubMed] [Google Scholar]
  4. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  5. Coffey R. J., Jr, Derynck R., Wilcox J. N., Bringman T. S., Goustin A. S., Moses H. L., Pittelkow M. R. Production and auto-induction of transforming growth factor-alpha in human keratinocytes. 1987 Aug 27-Sep 2Nature. 328(6133):817–820. doi: 10.1038/328817a0. [DOI] [PubMed] [Google Scholar]
  6. Coffey R. J., Jr, Sipes N. J., Bascom C. C., Graves-Deal R., Pennington C. Y., Weissman B. E., Moses H. L. Growth modulation of mouse keratinocytes by transforming growth factors. Cancer Res. 1988 Mar 15;48(6):1596–1602. [PubMed] [Google Scholar]
  7. Derynck R., Goeddel D. V., Ullrich A., Gutterman J. U., Williams R. D., Bringman T. S., Berger W. H. Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors. Cancer Res. 1987 Feb 1;47(3):707–712. [PubMed] [Google Scholar]
  8. Derynck R., Roberts A. B., Winkler M. E., Chen E. Y., Goeddel D. V. Human transforming growth factor-alpha: precursor structure and expression in E. coli. Cell. 1984 Aug;38(1):287–297. doi: 10.1016/0092-8674(84)90550-6. [DOI] [PubMed] [Google Scholar]
  9. Derynck R. Transforming growth factor alpha. Cell. 1988 Aug 26;54(5):593–595. doi: 10.1016/s0092-8674(88)80001-1. [DOI] [PubMed] [Google Scholar]
  10. Earp H. S., O'Keefe E. J. Epidermal growth factor receptor number decreases during rat liver regeneration. J Clin Invest. 1981 May;67(5):1580–1583. doi: 10.1172/JCI110190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fausto N., Mead J. E., Braun L., Thompson N. L., Panzica M., Goyette M., Bell G. I., Shank P. R. Proto-oncogene expression and growth factors during liver regeneration. Symp Fundam Cancer Res. 1986;39:69–86. [PubMed] [Google Scholar]
  12. GRISHAM J. W. A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating rat liver; autoradiography with thymidine-H3. Cancer Res. 1962 Aug;22:842–849. [PubMed] [Google Scholar]
  13. Hsieh L. L., Peraino C., Weinstein I. B. Expression of endogenous retrovirus-like sequences and cellular oncogenes during phenobarbital treatment and regeneration in rat liver. Cancer Res. 1988 Jan 15;48(2):265–269. [PubMed] [Google Scholar]
  14. Johnson A. C., Garfield S. H., Merlino G. T., Pastan I. Expression of epidermal growth factor receptor proto-oncogene mRNA in regenerating rat liver. Biochem Biophys Res Commun. 1988 Jan 15;150(1):412–418. doi: 10.1016/0006-291x(88)90536-0. [DOI] [PubMed] [Google Scholar]
  15. Liu C., Tsao M. S., Grisham J. W. Transforming growth factors produced by normal and neoplastically transformed rat liver epithelial cells in culture. Cancer Res. 1988 Feb 15;48(4):850–855. [PubMed] [Google Scholar]
  16. Madtes D. K., Raines E. W., Sakariassen K. S., Assoian R. K., Sporn M. B., Bell G. I., Ross R. Induction of transforming growth factor-alpha in activated human alveolar macrophages. Cell. 1988 Apr 22;53(2):285–293. doi: 10.1016/0092-8674(88)90390-x. [DOI] [PubMed] [Google Scholar]
  17. McMahon J. B., Richards W. L., del Campo A. A., Song M. K., Thorgeirsson S. S. Differential effects of transforming growth factor-beta on proliferation of normal and malignant rat liver epithelial cells in culture. Cancer Res. 1986 Sep;46(9):4665–4671. [PubMed] [Google Scholar]
  18. Merlino G. T., Ishii S., Whang-Peng J., Knutsen T., Xu Y. H., Clark A. J., Stratton R. H., Wilson R. K., Ma D. P., Roe B. A. Structure and localization of genes encoding aberrant and normal epidermal growth factor receptor RNAs from A431 human carcinoma cells. Mol Cell Biol. 1985 Jul;5(7):1722–1734. doi: 10.1128/MCB.5.7.1722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Michalopoulos G., Houck K. A., Dolan M. L., Leutteke N. C. Control of hepatocyte replication by two serum factors. Cancer Res. 1984 Oct;44(10):4414–4419. [PubMed] [Google Scholar]
  20. Nakamura T., Tomita Y., Hirai R., Yamaoka K., Kaji K., Ichihara A. Inhibitory effect of transforming growth factor-beta on DNA synthesis of adult rat hepatocytes in primary culture. Biochem Biophys Res Commun. 1985 Dec 31;133(3):1042–1050. doi: 10.1016/0006-291x(85)91241-0. [DOI] [PubMed] [Google Scholar]
  21. Norstedt G., Levinovitz A., Möller C., Eriksson L. C., Andersson G. Expression of insulin-like growth factor I (IGF-I) and IGF-II mRNA during hepatic development, proliferation and carcinogenesis in the rat. Carcinogenesis. 1988 Feb;9(2):209–213. doi: 10.1093/carcin/9.2.209. [DOI] [PubMed] [Google Scholar]
  22. Rall L. B., Scott J., Bell G. I., Crawford R. J., Penschow J. D., Niall H. D., Coghlan J. P. Mouse prepro-epidermal growth factor synthesis by the kidney and other tissues. Nature. 1985 Jan 17;313(5999):228–231. doi: 10.1038/313228a0. [DOI] [PubMed] [Google Scholar]
  23. Rappolee D. A., Mark D., Banda M. J., Werb Z. Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science. 1988 Aug 5;241(4866):708–712. doi: 10.1126/science.3041594. [DOI] [PubMed] [Google Scholar]
  24. Roberts A. B., Lamb L. C., Newton D. L., Sporn M. B., De Larco J. E., Todaro G. J. Transforming growth factors: isolation of polypeptides from virally and chemically transformed cells by acid/ethanol extraction. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3494–3498. doi: 10.1073/pnas.77.6.3494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Roberts A. B., Sporn M. B. Transforming growth factors. Cancer Surv. 1985;4(4):683–705. [PubMed] [Google Scholar]
  26. Russell W. E., Coffey R. J., Jr, Ouellette A. J., Moses H. L. Type beta transforming growth factor reversibly inhibits the early proliferative response to partial hepatectomy in the rat. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5126–5130. doi: 10.1073/pnas.85.14.5126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Russell W. E. Transforming growth factor beta (TGF-beta) inhibits hepatocyte DNA synthesis independently of EGF binding and EGF receptor autophosphorylation. J Cell Physiol. 1988 May;135(2):253–261. doi: 10.1002/jcp.1041350212. [DOI] [PubMed] [Google Scholar]
  28. Seglen P. O. Preparation of rat liver cells. 3. Enzymatic requirements for tissue dispersion. Exp Cell Res. 1973 Dec;82(2):391–398. doi: 10.1016/0014-4827(73)90357-1. [DOI] [PubMed] [Google Scholar]
  29. Skov Olsen P., Boesby S., Kirkegaard P., Therkelsen K., Almdal T., Poulsen S. S., Nexø E. Influence of epidermal growth factor on liver regeneration after partial hepatectomy in rats. Hepatology. 1988 Sep-Oct;8(5):992–996. doi: 10.1002/hep.1840080503. [DOI] [PubMed] [Google Scholar]
  30. Strain A. J., Frazer A., Hill D. J., Milner R. D. Transforming growth factor beta inhibits DNA synthesis in hepatocytes isolated from normal and regenerating rat liver. Biochem Biophys Res Commun. 1987 May 29;145(1):436–442. doi: 10.1016/0006-291x(87)91340-4. [DOI] [PubMed] [Google Scholar]
  31. Thompson N. L., Mead J. E., Braun L., Goyette M., Shank P. R., Fausto N. Sequential protooncogene expression during rat liver regeneration. Cancer Res. 1986 Jun;46(6):3111–3117. [PubMed] [Google Scholar]
  32. Yaswen P., Hayner N. T., Fausto N. Isolation of oval cells by centrifugal elutriation and comparison with other cell types purified from normal and preneoplastic livers. Cancer Res. 1984 Jan;44(1):324–331. [PubMed] [Google Scholar]

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