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. 1997 May 15;99(10):2365–2374. doi: 10.1172/JCI119418

Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells.

I Tachibana 1, M Imoto 1, P N Adjei 1, G J Gores 1, M Subramaniam 1, T C Spelsberg 1, R Urrutia 1
PMCID: PMC508075  PMID: 9153278

Abstract

Members of the TGFbeta family of peptides exert antiproliferative effects and induce apoptosis in epithelial cell populations. In the exocrine pancreas, these peptides not only regulate normal cell growth, but alterations in these pathways have been associated with neoplastic transformation. Therefore, the identification of molecules that regulate exocrine pancreatic cell proliferation and apoptotic cell death in response to TGFbeta peptides is necessary for a better understanding of normal morphogenesis as well as carcinogenesis of the pancreas. In this study, we have characterized the expression and function in exocrine pancreatic epithelial cells of the TGFbeta-inducible early gene (TIEG), a Krüppel-like zinc finger transcription factor encoding gene previously isolated from mesodermally derived osteoblastic cells. We demonstrate that this gene is expressed in both acinar and ductular epithelial cell populations from the exocrine pancreas. In addition, we show that the expression of TIEG is regulated by TGFbeta1 as an early response gene in pancreatic epithelial cell lines. Moreover, overexpression of TIEG in the TGFbeta-sensitive epithelial cell line PANC1 is sufficient to induce apoptosis. Together, these results support a role for TIEG in linking TGFbeta-mediated signaling cascades to the regulation of pancreatic epithelial cell growth.

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Selected References

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

  1. Alexandrow M. G., Moses H. L. Transforming growth factor beta and cell cycle regulation. Cancer Res. 1995 Apr 1;55(7):1452–1457. [PubMed] [Google Scholar]
  2. Baldwin R. L., Korc M. Growth inhibition of human pancreatic carcinoma cells by transforming growth factor beta-1. Growth Factors. 1993;8(1):23–34. doi: 10.3109/08977199309029131. [DOI] [PubMed] [Google Scholar]
  3. Centrella M., McCarthy T. L., Canalis E. Transforming growth factor-beta and remodeling of bone. J Bone Joint Surg Am. 1991 Oct;73(9):1418–1428. [PubMed] [Google Scholar]
  4. Chen Y. T., Holcomb C., Moore H. P. Expression and localization of two low molecular weight GTP-binding proteins, Rab8 and Rab10, by epitope tag. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6508–6512. doi: 10.1073/pnas.90.14.6508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chesnut J. D., Baytan A. R., Russell M., Chang M. P., Bernard A., Maxwell I. H., Hoeffler J. P. Selective isolation of transiently transfected cells from a mammalian cell population with vectors expressing a membrane anchored single-chain antibody. J Immunol Methods. 1996 Jun 14;193(1):17–27. doi: 10.1016/0022-1759(96)00032-4. [DOI] [PubMed] [Google Scholar]
  6. Chinnaiyan A. M., O'Rourke K., Tewari M., Dixit V. M. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995 May 19;81(4):505–512. doi: 10.1016/0092-8674(95)90071-3. [DOI] [PubMed] [Google Scholar]
  7. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  8. Cook T. A., Mesa K. J., Gebelein B. A., Urrutia R. A. Upregulation of dynamin II expression during the acquisition of a mature pancreatic acinar cell phenotype. J Histochem Cytochem. 1996 Dec;44(12):1373–1378. doi: 10.1177/44.12.8985129. [DOI] [PubMed] [Google Scholar]
  9. Cook T., Mesa K., Urrutia R. Three dynamin-encoding genes are differentially expressed in developing rat brain. J Neurochem. 1996 Sep;67(3):927–931. doi: 10.1046/j.1471-4159.1996.67030927.x. [DOI] [PubMed] [Google Scholar]
  10. Datto M. B., Yu Y., Wang X. F. Functional analysis of the transforming growth factor beta responsive elements in the WAF1/Cip1/p21 promoter. J Biol Chem. 1995 Dec 1;270(48):28623–28628. doi: 10.1074/jbc.270.48.28623. [DOI] [PubMed] [Google Scholar]
  11. Freeman J. W., Mattingly C. A., Strodel W. E. Increased tumorigenicity in the human pancreatic cell line MIA PaCa-2 is associated with an aberrant regulation of an IGF-1 autocrine loop and lack of expression of the TGF-beta type RII receptor. J Cell Physiol. 1995 Oct;165(1):155–163. doi: 10.1002/jcp.1041650118. [DOI] [PubMed] [Google Scholar]
  12. Friess H., Yamanaka Y., Büchler M., Berger H. G., Kobrin M. S., Baldwin R. L., Korc M. Enhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression. Cancer Res. 1993 Jun 15;53(12):2704–2707. [PubMed] [Google Scholar]
  13. Friess H., Yamanaka Y., Büchler M., Ebert M., Beger H. G., Gold L. I., Korc M. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology. 1993 Dec;105(6):1846–1856. doi: 10.1016/0016-5085(93)91084-u. [DOI] [PubMed] [Google Scholar]
  14. Gashler A., Sukhatme V. P. Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors. Prog Nucleic Acid Res Mol Biol. 1995;50:191–224. doi: 10.1016/s0079-6603(08)60815-6. [DOI] [PubMed] [Google Scholar]
  15. Gebelein B., Mesa K., Urrutia R. A novel profile of expressed sequence tags for zinc finger encoding genes from the poorly differentiated exocrine pancreatic cell line AR4IP. Cancer Lett. 1996 Aug 2;105(2):225–231. doi: 10.1016/0304-3835(96)04286-3. [DOI] [PubMed] [Google Scholar]
  16. Gress T., Müller-Pillasch F., Elsässer H. P., Bachem M., Ferrara C., Weidenbach H., Lerch M., Adler G. Enhancement of transforming growth factor beta 1 expression in the rat pancreas during regeneration from caerulein-induced pancreatitis. Eur J Clin Invest. 1994 Oct;24(10):679–685. doi: 10.1111/j.1365-2362.1994.tb01060.x. [DOI] [PubMed] [Google Scholar]
  17. Guan K. L. The mitogen activated protein kinase signal transduction pathway: from the cell surface to the nucleus. Cell Signal. 1994 Aug;6(6):581–589. doi: 10.1016/0898-6568(94)90041-8. [DOI] [PubMed] [Google Scholar]
  18. Hahn S. A., Schutte M., Hoque A. T., Moskaluk C. A., da Costa L. T., Rozenblum E., Weinstein C. L., Fischer A., Yeo C. J., Hruban R. H. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996 Jan 19;271(5247):350–353. doi: 10.1126/science.271.5247.350. [DOI] [PubMed] [Google Scholar]
  19. Hill C. S., Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 1995 Jan 27;80(2):199–211. doi: 10.1016/0092-8674(95)90403-4. [DOI] [PubMed] [Google Scholar]
  20. Hoodless P. A., Haerry T., Abdollah S., Stapleton M., O'Connor M. B., Attisano L., Wrana J. L. MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell. 1996 May 17;85(4):489–500. doi: 10.1016/s0092-8674(00)81250-7. [DOI] [PubMed] [Google Scholar]
  21. Krapivinsky G., Gordon E. A., Wickman K., Velimirović B., Krapivinsky L., Clapham D. E. The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins. Nature. 1995 Mar 9;374(6518):135–141. doi: 10.1038/374135a0. [DOI] [PubMed] [Google Scholar]
  22. Kreidberg J. A., Sariola H., Loring J. M., Maeda M., Pelletier J., Housman D., Jaenisch R. WT-1 is required for early kidney development. Cell. 1993 Aug 27;74(4):679–691. doi: 10.1016/0092-8674(93)90515-r. [DOI] [PubMed] [Google Scholar]
  23. Kwo P., Patel T., Bronk S. F., Gores G. J. Nuclear serine protease activity contributes to bile acid-induced apoptosis in hepatocytes. Am J Physiol. 1995 Apr;268(4 Pt 1):G613–G621. doi: 10.1152/ajpgi.1995.268.4.G613. [DOI] [PubMed] [Google Scholar]
  24. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  25. Lee M. S., Gu D., Feng L., Curriden S., Arnush M., Krahl T., Gurushanthaiah D., Wilson C., Loskutoff D. L., Fox H. Accumulation of extracellular matrix and developmental dysregulation in the pancreas by transgenic production of transforming growth factor-beta 1. Am J Pathol. 1995 Jul;147(1):42–52. [PMC free article] [PubMed] [Google Scholar]
  26. Li J. M., Nichols M. A., Chandrasekharan S., Xiong Y., Wang X. F. Transforming growth factor beta activates the promoter of cyclin-dependent kinase inhibitor p15INK4B through an Sp1 consensus site. J Biol Chem. 1995 Nov 10;270(45):26750–26753. doi: 10.1074/jbc.270.45.26750. [DOI] [PubMed] [Google Scholar]
  27. Martikainen P., Kyprianou N., Isaacs J. T. Effect of transforming growth factor-beta 1 on proliferation and death of rat prostatic cells. Endocrinology. 1990 Dec;127(6):2963–2968. doi: 10.1210/endo-127-6-2963. [DOI] [PubMed] [Google Scholar]
  28. McConkey D. J., Orrenius S. Signal transduction pathways to apoptosis. Trends Cell Biol. 1994 Oct;4(10):370–375. doi: 10.1016/0962-8924(94)90087-6. [DOI] [PubMed] [Google Scholar]
  29. Meisenholder G. W., Martin S. J., Green D. R., Nordberg J., Babior B. M., Gottlieb R. A. Events in apoptosis. Acidification is downstream of protease activation and BCL-2 protection. J Biol Chem. 1996 Jul 5;271(27):16260–16262. doi: 10.1074/jbc.271.27.16260. [DOI] [PubMed] [Google Scholar]
  30. Mesa K., Gebelein B., Cook T., Urrutia R. Identification and characterization of zinc finger encoding genes from the tumoral exocrine pancreatic cell line AR42J. Cancer Lett. 1996 Jun 5;103(2):143–149. doi: 10.1016/0304-3835(96)04204-8. [DOI] [PubMed] [Google Scholar]
  31. Oberhammer F. A., Pavelka M., Sharma S., Tiefenbacher R., Purchio A. F., Bursch W., Schulte-Hermann R. Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor beta 1. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5408–5412. doi: 10.1073/pnas.89.12.5408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Patel T., Bronk S. F., Gores G. J. Increases of intracellular magnesium promote glycodeoxycholate-induced apoptosis in rat hepatocytes. J Clin Invest. 1994 Dec;94(6):2183–2192. doi: 10.1172/JCI117579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rotello R. J., Lieberman R. C., Purchio A. F., Gerschenson L. E. Coordinated regulation of apoptosis and cell proliferation by transforming growth factor beta 1 in cultured uterine epithelial cells. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3412–3415. doi: 10.1073/pnas.88.8.3412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sanvito F., Herrera P. L., Huarte J., Nichols A., Montesano R., Orci L., Vassalli J. D. TGF-beta 1 influences the relative development of the exocrine and endocrine pancreas in vitro. Development. 1994 Dec;120(12):3451–3462. doi: 10.1242/dev.120.12.3451. [DOI] [PubMed] [Google Scholar]
  35. Sanvito F., Nichols A., Herrera P. L., Huarte J., Wohlwend A., Vassalli J. D., Orci L. TGF-beta 1 overexpression in murine pancreas induces chronic pancreatitis and, together with TNF-alpha, triggers insulin-dependent diabetes. Biochem Biophys Res Commun. 1995 Dec 26;217(3):1279–1286. doi: 10.1006/bbrc.1995.2906. [DOI] [PubMed] [Google Scholar]
  36. Sekelsky J. J., Newfeld S. J., Raftery L. A., Chartoff E. H., Gelbart W. M. Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics. 1995 Mar;139(3):1347–1358. doi: 10.1093/genetics/139.3.1347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Slater S. D., Williamson R. C., Foster C. S. Expression of transforming growth factor-beta 1 in chronic pancreatitis. Digestion. 1995;56(3):237–241. doi: 10.1159/000201249. [DOI] [PubMed] [Google Scholar]
  38. Sporn M. B., Roberts A. B. Transforming growth factor-beta: recent progress and new challenges. J Cell Biol. 1992 Dec;119(5):1017–1021. doi: 10.1083/jcb.119.5.1017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Subramaniam M., Harris S. A., Oursler M. J., Rasmussen K., Riggs B. L., Spelsberg T. C. Identification of a novel TGF-beta-regulated gene encoding a putative zinc finger protein in human osteoblasts. Nucleic Acids Res. 1995 Dec 11;23(23):4907–4912. doi: 10.1093/nar/23.23.4907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Urrutia R., McNiven M. A., Albanesi J. P., Murphy D. B., Kachar B. Purified kinesin promotes vesicle motility and induces active sliding between microtubules in vitro. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6701–6705. doi: 10.1073/pnas.88.15.6701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yingling J. M., Wang X. F., Bassing C. H. Signaling by the transforming growth factor-beta receptors. Biochim Biophys Acta. 1995 Dec 18;1242(2):115–136. doi: 10.1016/0304-419x(95)00007-2. [DOI] [PubMed] [Google Scholar]
  43. Zhang Y., Feng X., We R., Derynck R. Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature. 1996 Sep 12;383(6596):168–172. doi: 10.1038/383168a0. [DOI] [PubMed] [Google Scholar]
  44. van Laethem J. L., Deviere J., Resibois A., Rickaert F., Vertongen P., Ohtani H., Cremer M., Miyazono K., Robberecht P. Localization of transforming growth factor beta 1 and its latent binding protein in human chronic pancreatitis. Gastroenterology. 1995 Jun;108(6):1873–1881. doi: 10.1016/0016-5085(95)90152-3. [DOI] [PubMed] [Google Scholar]

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