Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Analysis of the human proopiomelanocortin gene promoter in a small cell lung carcinoma cell line reveals an unusual role for E2F transcription factors

Abstract

The small cell lung carcinoma (SCLC) cell line DMS-79 has been used as a model for studying the molecular mechanism underlying the ectopic ACTH syndrome. We previously showed that two domains of the human Proopiomelanocortin (POMC) gene promoter were specifically active in DMS-79 cells. The present study focuses on the more distal one, Domain IV (−376/−417). DNaseI footprinting experiments identified a single binding site for DMS-79 cell proteins in this domain. Gel-shift and sequence analysis indicated that E2F proteins might bind this site. Indeed, proteins from DMS-79 cells which bind this site (i) have in vitro DNA binding properties indistinguishable from those of E2F proteins (ii) form, like E2F proteins, multiprotein complexes which can be dissociated by sodium deoxycholate and (iii) are recognized by antibodies directed against E2F proteins. Further, we show that the rat POMC distal promoter domain contains a homologous sequence which constitutes a natural mutant of the human POMC E2F binding site, since it does not bind E2F. We show by transient transfection that this natural mutant, in the context of the rat POMC promoter, is not active in DMS-79 cells by contrast to the human POMC E2F binding site. We conclude that E2F binding is required for the activity of Domain IV in DMS-79 cells and contributes to the expression of the POMC gene in SCLC. Further studies are required to elucidate the role of E2F factors in POMC gene transcription in SCLC cells, but our results have identified mechanisms different from those in pituitary corticotroph cells that are used by these SCLC tumor cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Abe K, Kameya T, Yamaguchi K, Kikuchi K, Adachi I, Tanaka M, Kimura S, Kodama T, Shimosato Y and Ishikawa S. . 1984 In: The endocrine lung in health and disease. WB Saunders Company: New York pp.549–595.

    Google Scholar 

  • Baylin SB and Mendelsohn G. . 1980 Endocr. Rev. 1: 45–77.

  • Becker KL and Gazdar AF. . 1984 In: The endocrine lung in health and disease. WB Saunders Company.

    Google Scholar 

  • Bertagna X, Nicholson WE, Sorenson GD, Pettengill OS, Mount CD and Orth DN. . 1978 Proc. Natl. Acad. Sci. USA 75: 5160–5164.

  • de Keyzer Y, Bertagna X, Lenne F, Girard F, Luton J-P and Kahn A. . 1985 J. Clin. Invest. 76: 1892–1898.

    Article  CAS  Google Scholar 

  • de Keyzer Y, Vieau D, Picon A and Bertagna X. . 1996 Endocr. Rel. Cancer 3: 99–112.

  • Gaitan D, DeBold CR, Turney MK, Zhou P, Orth DN and Kovacs WJ. . 1995 Mol. Endocrinol. 9: 1193–1201.

  • Gould VE, Warren WH and Memoli VA. . 1984 In: The endocrine lung in health and disease. Becker KL and Gazdar AF (eds).. WB Saunders Company: New York pp.406–445.

    Google Scholar 

  • Hammer GD, Fairchild-Huntress V and Low MJ. . 1990 Mol. Endocrinol. 4: 1689–1697.

  • Harbour JW, Lai S-L, Whang-Peng J, Gazdar AF, Minna JD and Kaye FJ. . 1988 Science 241: 353–357.

    Article  CAS  Google Scholar 

  • Hedvat CV and Irving SG. . 1995 Mol. Endocrinol. 9: 1692–1700.

  • Helin K, Lees JA, Vidal M, Dyson N, Harlow E and Fattaey A. . 1992 Cell 70: 337–350.

    Article  CAS  Google Scholar 

  • Helin K, Wu C-L, Fattaey AR, Lees JA, Dynlacht BD, Ngwu C and Harlow E. . 1993 Genes Dev. 7: 1850–1861.

  • Helin K, Holm K, Niebuhr A, Eiberg H, Tommerup N, Hougaard S, Skovgaard Poulsen H, Spang-Thomsen M and Norgaard P. . 1997 Proc. Natl. Acad. Sci. USA 94: 6933–6938.

  • Jeannotte L, Trifiro MA, Plante RK, Chamberland M and Drouin J. . 1987 Mol. Cell. Biol. 7: 4058–4064.

    Article  CAS  Google Scholar 

  • Lam EW-F and La Thangue NB. . 1994 Curr. Opin. Cell. Biol. 6: 859–866.

  • Lamonerie T, Tremblay JJ, Lanctôt C, Therrien M, Gauthier Y and Drouin J. . 1996 Genes Dev. 10: 1284–1295.

  • Loiseau L, Pasteau S and Brun G. . 1997 Gene Expr. 6: 259–273.

  • Maxam AM and Gilbert W. . 1980 Methods Enzymol. 65: 499–560.

  • Murphy EP and Conneely OM. . 1997 Mol. Endocrinol. 11: 39–47.

  • Okabe T, Takayanagi R, Adachi M, Imasaki K and Nawata H. . 1998 J. Endocrinol. 156: 169–175.

  • Orth DN. . 1995 N. Engl. J. Med. 332: 791–803.

  • Philips A, Lesage S, Gingras R, Maira M-H, Gauthier Y, Hugo P and Drouin J. . 1997 Mol. Cell. Biol. 17: 5946–5951.

    Article  CAS  Google Scholar 

  • Picon A, Leblond-Francillard M, Raffin-Sanson M-L, Lenne F, Bertagna X and de Keyzer Y. . 1995 J. Mol. Endo. 15: 187–194.

  • Poulin G, Turgeon B and Drouin J. . 1997 Mol. Cell. Biol. 17: 6673–6682.

    Article  CAS  Google Scholar 

  • Raymondjean M, Cereghini S and Yaniv M. . 1988 Proc. Natl. Acad. Sci. USA 85: 757–761.

  • Rygaard K, Sorenson GD, Pettengill OS, Cate CC and Spang-Thomsen M. . 1990 Cancer Res. 50: 5312–5317.

  • Sambrook J, Fritsch EF and Maniatis T. . 1989 In: Molecular cloning: A laboratory manual. Cold Spring Harbor: Cold Spring Harbor Laboratory Press.

    Google Scholar 

  • Slansky JE and Farnham PJ. . 1996 Curr. Top. Microbiol. Immunol. 208: 1–30.

  • Sorenson GD, Pettengill OS, Brinck-Johnsen T, Cate CC and Maurer LH. . 1981 Cancer 47: 1289–1296.

    Article  CAS  Google Scholar 

  • Therrien M and Drouin J. . 1991 Mol. Cell. Biol. 11: 3492–3503.

    Article  CAS  Google Scholar 

  • Therrien M and Drouin J. . 1993 Mol. Cell. Biol. 13: 2342–2353.

    Article  CAS  Google Scholar 

  • Tremblay Y, Tretjakoff I, Peterson A, Antakly T, Zhang CX and Drouin J. . 1988 Proc. Natl. Acad. Sci. USA 85: 8890–8894.

  • Wajchenberg BL, Mendonca BB, Liberman B, Albergaria-Pereira MA, Carneiro PC, Wakamatsu A and Kirschner MA. . 1994 Endocr. Rev. 15: 752–787.

  • Wilson TE, Fahrner TJ, Johnston M and Milbrandt J. . 1991 Science 252: 1296–1300.

    Article  CAS  Google Scholar 

  • Wong K-K, Zou X, Merrell KT, Patel AJ, Marcu KB, Chellapan S and Calame K. . 1995 Mol. Cell. Biol. 15: 6535–6544.

    Article  CAS  Google Scholar 

  • Yee AS, Reichel R, Kovesdi I and Nevins JR. . 1987 EMBO J. 6: 2061–2068.

Download references

Acknowledgements

We are indebted to Dr GD Sorenson and Dr O Pettengill for having provided us with the DMS-79 cell line. We wish to thank Drs DN Orth for his valuable comments on the manuscript and M Raymondjean for helpful discussions and comments. We thank Dr J Drouin for rat POMC plasmids and Drs G Brun and L Loiseau for chDP-1 and chE2F-1 plasmids. This work was supported in part by INSERM CJF92-08 and the Association pour la Recherche Contre le Cancer, (contract 6501 to YdK). A Picon is the recipient of a doctoral fellowship of the Association pour la Recherche Contre le Cancer.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Picon, A., Bertagna, X. & de Keyzer, Y. Analysis of the human proopiomelanocortin gene promoter in a small cell lung carcinoma cell line reveals an unusual role for E2F transcription factors. Oncogene 18, 2627–2633 (1999). https://doi.org/10.1038/sj.onc.1202635

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202635

Keywords

This article is cited by

Search

Quick links