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.

Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma

Abstract

Transgenic mouse models have provided evidence that activation of the zinc-finger transcription factor GLI1 by Hedgehog (Hh)-signalling is a key step in the initiation of the tumorigenic programme leading to Basal Cell Carcinoma (BCC). However, the downstream events underlying Hh/GLI-induced BCC development are still obscure. Using in vitro model systems to analyse the effect of Hh/GLI-signalling in human keratinocytes, we identified a positive feedback mechanism involving the zinc finger transcription factors GLI1 and GLI2. Expression of GLI1 in human keratinocytes induced the transcriptional activator isoforms GLI2α and GLI2β. Both isoforms were also shown to be expressed at elevated levels in 21 BCCs compared to normal skin. Detailed time course experiments monitoring the transcriptional response of keratinocytes either to GLI1 or to GLI2 suggest that GLI1 is a direct target of GLI2, while activation of GLI2 by GLI1 is likely to be indirect. Furthermore, expression of either GLI2 or GLI1 led to an increase in DNA-synthesis in confluent human keratinocytes. Taken together, these results suggest an important role of the positive GLI1-GLI2 feedback loop in Hh-mediated epidermal cell proliferation.

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

Relevant articles

Open Access articles citing this article.

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

References

  • Altaba AR . 1999 Development 126: 3205–3216

  • Aszterbaum M, Epstein J, Oro A, Douglas V, LeBoit PE, Scott MP, Epstein Jr EH . 1999 Nat. Med. 5: 1285–1291

  • Aza-Blanc P, Lin HY, Ruiz i Altaba A, Kornberg TB . 2000 Development 127: 4293–4301

  • Bai CB, Joyner AL . 2001 Development 128: 5161–5172

  • Bonifas JM, Pennypacker S, Chuang PT, McMahon AP, Williams M, Rosenthal A, De Sauvage FJ, Epstein Jr EH . 2001 J. Invest. Dermatol. 116: 739–742

  • Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE . 1988 J. Cell. Biol. 106: 761–771

  • Dahmane N, Lee J, Robins P, Heller P, Ruiz i Altaba A . 1997 Nature 389: 876–881

  • Dahmane N, Sanchez P, Gitton Y, Palma V, Sun T, Beyna M, Weiner H, Ruiz i Altaba A . 2001 Development 128: 5201–5212

  • Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S . 1999 J. Biol. Chem. 274: 8143–8152

  • Deng H, Lin Q, Khavari PA . 1997 Nat. Biotechnol. 15: 1388–1391

  • Ding Q, Motoyama J, Gasca S, Mo R, Sasaki H, Rossant J, Hui CC . 1998 Development 125: 2533–2543

  • Fan H, Khavari PA . 1999 J. Cell. Biol. 147: 71–76

  • Fan H, Oro AE, Scott MP, Khavari PA . 1997 Nat. Med. 3: 788–792

  • Gailani MR, Stahle-Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, Toftgard R . 1996 Nat. Genet. 14: 78–81

  • Ghali L, Wong ST, Green J, Tidman N, Quinn AG . 1999 J. Invest. Dermatol. 113: 595–599

  • Goodrich LV, Scott MP . 1998 Neuron 21: 1243–1257

  • Grachtchouk M, Mo R, Yu S, Zhang X, Sasaki H, Hui CC, Dlugosz AA . 2000 Nat. Genet. 24: 216–217

  • Green J, Leigh IM, Poulsom R, Quinn AG . 1998 Br. J. Dermatol. 139: 911–915

  • Hahn H, Christiansen J, Wicking C, Zaphiropoulos PG, Chidambaram A, Gerrard B, Vorechovsky I, Bale AE, Toftgard R, Dean M, Wainwright B . 1996 J. Biol. Chem. 271: 12125–12128

  • Hahn H, Wojnowski L, Miller G, Zimmer A . 1999 J. Mol. Med. 77: 459–468

  • Hardcastle Z, Mo R, Hui CC, Sharpe PT . 1998 Development 125: 2803–2811

  • Hynes M, Stone DM, Dowd M, Pitts-Meek S, Goddard A, Gurney A, Rosenthal A . 1997 Neuron 19: 15–26

  • i Altaba AR . 1998 Development 125: 2203–2212

  • Ingham PW . 1998 EMBO J. 17: 3505–3511

  • Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein Jr EH, Scott MP . 1996 Science 272: 1668–1671

  • Kinto N, Iwamoto M, Enomoto-Iwamoto M, Noji S, Ohuchi H, Yoshioka H, Kataoka H, Wada Y, Yuhao G, Takahashi HE, Yoshiki S, Yamaguchi A . 1997 FEBS. Lett. 404: 319–323

  • Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O'Brien SJ, Wong AJ, Vogelstein B . 1987 Science 236: 70–73

  • Liu CZ, Yang JT, Yoon JW, Villavicencio E, Pfendler K, Walterhouse D, Iannaccone P . 1998 Gene 209: 1–11

  • Martin KJ, Graner E, Li Y, Price LM, Kritzman BM, Fournier MV, Rhei E, Pardee AB . 2001 Proc. Natl. Acad. Sci. USA 98: 2646–2651

  • Matise MP, Epstein DJ, Park HL, Platt KA, Joyner AL . 1998 Development 125: 2759–2770

  • Matise MP, Joyner AL . 1999 Oncogene 18: 7852–7859

  • Mo R, Freer AM, Zinyk DL, Crackower MA, Michaud J, Heng HH, Chik KW, Shi XM, Tsui LC, Cheng SH, Joyner AL, Hui C . 1997 Development 124: 113–123

  • Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC . 1998 Nat. Genet. 20: 54–57

  • Mullor JL, Dahmane N, Sun T, Ruiz i Altaba A . 2001 Curr. Biol. 11: 769–773

  • Murone M, Rosenthal A, de Sauvage FJ . 1999 Curr. Biol. 9: 76–84

  • Nilsson M, Unden AB, Krause D, Malmqwist U, Raza K, Zaphiropoulos PG, Toftgard R . 2000 Proc. Natl. Acad. Sci. USA 97: 3438–3443

  • Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein Jr EH, Scott MP . 1997 Science 276: 817–821

  • Park HL, Bai C, Platt KA, Matise MP, Beeghly A, Hui CC, Nakashima M, Joyner AL . 2000 Development 127: 1593–1605

  • Rheinwald JG, Green H . 1975 Cell 6: 331–343

  • Ruiz i Altaba A . 1999 Trends Genet. 15: 418–425

  • Ruppert JM, Kinzler KW, Wong AJ, Bigner SH, Kao FT, Law ML, Seuanez HN, O'Brien SJ, Vogelstein B . 1988 Mol. Cell. Biol. 8: 3104–3113

  • Ruppert JM, Vogelstein B, Kinzler KW . 1991 Mol. Cell. Biol. 11: 1724–1728

  • Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H . 1999 Development 126: 3915–3924

  • Shin SH, Kogerman P, Lindstrom E, Toftgard R, Biesecker LG . 1999 Proc. Natl. Acad. Sci. USA 96: 2880–2884

  • Tanimura A, Dan S, Yoshida M . 1998 J. Virol. 72: 3958–3964

  • Toftgard R . 2000 Cell Mol. Life Sci. 57: 1720–1731

  • Villavicencio EH, Walterhouse DO, Iannaccone PM . 2000 Am. J. Hum. Genet. 67: 1047–1054

  • Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein Jr EH, de Sauvage FJ . 1998 Nature 391: 90–92

Download references

Acknowledgements

We thank Dr Ken Kinzler for the gift of GLI1 plasmid, Dr Paul Khavari for Sin-IP-GFP plasmid, Dr David Markovitz for providing human GLI2β expression plasmid, Dr Gary Nolan for the permission to use the Phoenix packaging cell line and Dr Norbert Fusenig for providing the HaCaT cell line. We are particularly grateful to Dr Harald Esterbauer for his advice and discussions about real-time PCR analysis and to Dr Emberger for histopathological analysis of BCC samples. This work was supported by FWF grant P14227-MOB (Austria), and the Medical Research Council (UK).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fritz Aberger.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Regl, G., Neill, G., Eichberger, T. et al. Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma. Oncogene 21, 5529–5539 (2002). https://doi.org/10.1038/sj.onc.1205748

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205748

Keywords

This article is cited by

Search

Quick links