Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1996 May;73(9):1037–1043. doi: 10.1038/bjc.1996.201

Expression and autoregulation of transforming growth factor beta receptor mRNA in small-cell lung cancer cell lines.

P Nørgaard 1, M Spang-Thomsen 1, H S Poulsen 1
PMCID: PMC2074389  PMID: 8624260

Abstract

In small-cell lung cancer cell lines resistance to growth inhibition by transforming growth factor (TGF)-beta 1, was previously shown to correlate with lack of TGF-beta receptor I (RI) and II (RII) proteins. To further investigate the role of these receptors, the expression of mRNA for RI, RII and beta-glycan (RIII) was examined. The results showed that loss of RII mRNA correlated with TGF-beta 1 resistance. In contrast, RI-and beta-glycan mRNA was expressed by all cell lines, including those lacking expression of these proteins. According to Southern blot analysis, the loss of type II mRNA was not due to gross structural changes in the gene. The effect of TGF-beta 1 on expression of TGF-beta receptor mRNA (receptor autoregulation) was examined by quantitative Northern blotting in four cell lines with different expression of TGF-beta receptor proteins. In two cell lines expressing all three TGF-beta receptor proteins beta-glycan mRNA was rapidly down-regulated and this effect was sustained throughout the 24 h observation period. RI and RII mRNAs were slightly increased 24 h after treatment. In one cell line sensitive to growth inhibition by TGF-beta, 1 but lacking beta-glycan expression, and one cell line expressing only beta-glycan and thus TGF-beta 1 -resistant, no autoregulation of mRNA of either TGF-beta receptor was demonstrated. The results suggest that TGF-beta 1 regulates the expression of its receptors, in particular beta-glycan, and that this effect is dependent on co-expression of beta-glycan, RI and RII.

Full text

PDF
1040

Images in this article

1039Figure 1
on p.1039
1040Figure 2
on p.1040
1042Figure 4
on p.1042

Selected References

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

  1. Assoian R. K., Frolik C. A., Roberts A. B., Miller D. M., Sporn M. B. Transforming growth factor-beta controls receptor levels for epidermal growth factor in NRK fibroblasts. Cell. 1984 Jan;36(1):35–41. doi: 10.1016/0092-8674(84)90071-0. [DOI] [PubMed] [Google Scholar]
  2. Attisano L., Cárcamo J., Ventura F., Weis F. M., Massagué J., Wrana J. L. Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell. 1993 Nov 19;75(4):671–680. doi: 10.1016/0092-8674(93)90488-c. [DOI] [PubMed] [Google Scholar]
  3. Attisano L., Wrana J. L., López-Casillas F., Massagué J. TGF-beta receptors and actions. Biochim Biophys Acta. 1994 May 26;1222(1):71–80. doi: 10.1016/0167-4889(94)90026-4. [DOI] [PubMed] [Google Scholar]
  4. Berendsen H. H., de Leij L., de Vries E. G., Mesander G., Mulder N. H., de Jong B., Buys C. H., Postmus P. E., Poppema S., Sluiter H. J. Characterization of three small cell lung cancer cell lines established from one patient during longitudinal follow-up. Cancer Res. 1988 Dec 1;48(23):6891–6899. [PubMed] [Google Scholar]
  5. Boyd F. T., Massagué J. Transforming growth factor-beta inhibition of epithelial cell proliferation linked to the expression of a 53-kDa membrane receptor. J Biol Chem. 1989 Feb 5;264(4):2272–2278. [PubMed] [Google Scholar]
  6. 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]
  7. Damstrup L., Rygaard K., Spang-Thomsen M., Skovgaard Poulsen H. Expression of transforming growth factor beta (TGF beta) receptors and expression of TGF beta 1, TGF beta 2 and TGF beta 3 in human small cell lung cancer cell lines. Br J Cancer. 1993 May;67(5):1015–1021. doi: 10.1038/bjc.1993.186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ebner R., Chen R. H., Shum L., Lawler S., Zioncheck T. F., Lee A., Lopez A. R., Derynck R. Cloning of a type I TGF-beta receptor and its effect on TGF-beta binding to the type II receptor. Science. 1993 May 28;260(5112):1344–1348. doi: 10.1126/science.8388127. [DOI] [PubMed] [Google Scholar]
  9. Edwards D. R., Parfett C. L., Denhardt D. T. Transcriptional regulation of two serum-induced RNAs in mouse fibroblasts: equivalence of one species to B2 repetitive elements. Mol Cell Biol. 1985 Nov;5(11):3280–3288. doi: 10.1128/mcb.5.11.3280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Engelholm S. A., Spang-Thomsen M., Vindeløv L. L., Brünner N., Nielsen M. H., Hirsch F., Nielsen A., Hansen H. H. Comparison of characteristics of human small cell carcinoma of the lung in patients, in vitro and transplanted into nude mice. Acta Pathol Microbiol Immunol Scand A. 1986 Sep;94(5):325–336. doi: 10.1111/j.1699-0463.1986.tb03001.x. [DOI] [PubMed] [Google Scholar]
  11. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  12. Franzén P., ten Dijke P., Ichijo H., Yamashita H., Schulz P., Heldin C. H., Miyazono K. Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor. Cell. 1993 Nov 19;75(4):681–692. doi: 10.1016/0092-8674(93)90489-d. [DOI] [PubMed] [Google Scholar]
  13. Geiser A. G., Burmester J. K., Webbink R., Roberts A. B., Sporn M. B. Inhibition of growth by transforming growth factor-beta following fusion of two nonresponsive human carcinoma cell lines. Implication of the type II receptor in growth inhibitory responses. J Biol Chem. 1992 Feb 5;267(4):2588–2593. [PubMed] [Google Scholar]
  14. Inagaki M., Moustakas A., Lin H. Y., Lodish H. F., Carr B. I. Growth inhibition by transforming growth factor beta (TGF-beta) type I is restored in TGF-beta-resistant hepatoma cells after expression of TGF-beta receptor type II cDNA. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5359–5363. doi: 10.1073/pnas.90.11.5359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Inagaki M., Wang Z., Carr B. I. Transforming growth factor beta 1 selectively increases gene expression of the serine/threonine kinase receptor 1 (SKR1) in human hepatoma cell lines. Cell Struct Funct. 1994 Oct;19(5):305–313. doi: 10.1247/csf.19.305. [DOI] [PubMed] [Google Scholar]
  16. Kadin M. E., Cavaille-Coll M. W., Gertz R., Massagué J., Cheifetz S., George D. Loss of receptors for transforming growth factor beta in human T-cell malignancies. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6002–6006. doi: 10.1073/pnas.91.13.6002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kingsley D. M. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 1994 Jan;8(2):133–146. doi: 10.1101/gad.8.2.133. [DOI] [PubMed] [Google Scholar]
  18. Laiho M., Weis F. M., Boyd F. T., Ignotz R. A., Massagué J. Responsiveness to transforming growth factor-beta (TGF-beta) restored by genetic complementation between cells defective in TGF-beta receptors I and II. J Biol Chem. 1991 May 15;266(14):9108–9112. [PubMed] [Google Scholar]
  19. Leof E. B., Proper J. A., Goustin A. S., Shipley G. D., DiCorleto P. E., Moses H. L. Induction of c-sis mRNA and activity similar to platelet-derived growth factor by transforming growth factor beta: a proposed model for indirect mitogenesis involving autocrine activity. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2453–2457. doi: 10.1073/pnas.83.8.2453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lin H. Y., Wang X. F., Ng-Eaton E., Weinberg R. A., Lodish H. F. Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell. 1992 Feb 21;68(4):775–785. doi: 10.1016/0092-8674(92)90152-3. [DOI] [PubMed] [Google Scholar]
  21. López-Casillas F., Cheifetz S., Doody J., Andres J. L., Lane W. S., Massagué J. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system. Cell. 1991 Nov 15;67(4):785–795. doi: 10.1016/0092-8674(91)90073-8. [DOI] [PubMed] [Google Scholar]
  22. López-Casillas F., Wrana J. L., Massagué J. Betaglycan presents ligand to the TGF beta signaling receptor. Cell. 1993 Jul 2;73(7):1435–1444. doi: 10.1016/0092-8674(93)90368-z. [DOI] [PubMed] [Google Scholar]
  23. Markowitz S., Wang J., Myeroff L., Parsons R., Sun L., Lutterbaugh J., Fan R. S., Zborowska E., Kinzler K. W., Vogelstein B. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995 Jun 2;268(5215):1336–1338. doi: 10.1126/science.7761852. [DOI] [PubMed] [Google Scholar]
  24. Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641. doi: 10.1146/annurev.cb.06.110190.003121. [DOI] [PubMed] [Google Scholar]
  25. Morén A., Ichijo H., Miyazono K. Molecular cloning and characterization of the human and porcine transforming growth factor-beta type III receptors. Biochem Biophys Res Commun. 1992 Nov 30;189(1):356–362. doi: 10.1016/0006-291x(92)91566-9. [DOI] [PubMed] [Google Scholar]
  26. Moses H. L. TGF-beta regulation of epithelial cell proliferation. Mol Reprod Dev. 1992 Jun;32(2):179–184. doi: 10.1002/mrd.1080320215. [DOI] [PubMed] [Google Scholar]
  27. Moustakas A., Lin H. Y., Henis Y. I., Plamondon J., O'Connor-McCourt M. D., Lodish H. F. The transforming growth factor beta receptors types I, II, and III form hetero-oligomeric complexes in the presence of ligand. J Biol Chem. 1993 Oct 25;268(30):22215–22218. [PubMed] [Google Scholar]
  28. Nørgaard P., Damstrup L., Rygaard K., Spang-Thomsen M., Skovgaard Poulsen H. Growth suppression by transforming growth factor beta 1 of human small-cell lung cancer cell lines is associated with expression of the type II receptor. Br J Cancer. 1994 May;69(5):802–808. doi: 10.1038/bjc.1994.158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nørgaard P., Hougaard S., Poulsen H. S., Spang-Thomsen M. Transforming growth factor beta and cancer. Cancer Treat Rev. 1995 Jul;21(4):367–403. doi: 10.1016/0305-7372(95)90038-1. [DOI] [PubMed] [Google Scholar]
  30. Park K., Kim S. J., Bang Y. J., Park J. G., Kim N. K., Roberts A. B., Sporn M. B. Genetic changes in the transforming growth factor beta (TGF-beta) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8772–8776. doi: 10.1073/pnas.91.19.8772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pettengill O. S., Sorenson G. D., Wurster-Hill D. H., Curphey T. J., Noll W. W., Cate C. C., Maurer L. H. Isolation and growth characteristics of continuous cell lines from small-cell carcinoma of the lung. Cancer. 1980 Mar 1;45(5):906–918. doi: 10.1002/1097-0142(19800301)45:5<906::aid-cncr2820450513>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  32. Van Obberghen-Schilling E., Roche N. S., Flanders K. C., Sporn M. B., Roberts A. B. Transforming growth factor beta 1 positively regulates its own expression in normal and transformed cells. J Biol Chem. 1988 Jun 5;263(16):7741–7746. [PubMed] [Google Scholar]
  33. Wang X. F., Lin H. Y., Ng-Eaton E., Downward J., Lodish H. F., Weinberg R. A. Expression cloning and characterization of the TGF-beta type III receptor. Cell. 1991 Nov 15;67(4):797–805. doi: 10.1016/0092-8674(91)90074-9. [DOI] [PubMed] [Google Scholar]
  34. Wrana J. L., Attisano L., Cárcamo J., Zentella A., Doody J., Laiho M., Wang X. F., Massagué J. TGF beta signals through a heteromeric protein kinase receptor complex. Cell. 1992 Dec 11;71(6):1003–1014. doi: 10.1016/0092-8674(92)90395-s. [DOI] [PubMed] [Google Scholar]
  35. Wrana J. L., Attisano L., Wieser R., Ventura F., Massagué J. Mechanism of activation of the TGF-beta receptor. Nature. 1994 Aug 4;370(6488):341–347. doi: 10.1038/370341a0. [DOI] [PubMed] [Google Scholar]
  36. de Leij L., Postmus P. E., Buys C. H., Elema J. D., Ramaekers F., Poppema S., Brouwer M., van der Veen A. Y., Mesander G., The T. H. Characterization of three new variant type cell lines derived from small cell carcinoma of the lung. Cancer Res. 1985 Dec;45(12 Pt 1):6024–6033. [PubMed] [Google Scholar]
  37. ten Dijke P., Yamashita H., Ichijo H., Franzén P., Laiho M., Miyazono K., Heldin C. H. Characterization of type I receptors for transforming growth factor-beta and activin. Science. 1994 Apr 1;264(5155):101–104. doi: 10.1126/science.8140412. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES