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  • Original Paper
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Alternative first exons of PTCH1 are differentially regulated in vivo and may confer different functions to the PTCH1 protein

Oncogene volume 21, pages 6007–6016 (2002)Cite this article

Abstract

The PTCH1 gene is a human tumour suppressor gene frequently mutated in basal cell carcinoma (BCC) and several other tumour types. It encodes a receptor for soluble factors of the hedgehog family. Binding of hedgehog to the receptor relieves its inhibitory action on the transmembrane co-receptor Smoh. In this study we describe alternative first exons of the PTCH1 tumour suppressor gene and show that they are differentially regulated in normal tissues, exon 1B being expressed at very low levels and the major mRNA species containing exon 1 or 1A. Exon 1B transcripts were found to be specifically upregulated in nodular BCCs. The different PTCH1 transcripts all encode proteins that interact with Smoh in doubly transfected cells. Furthermore, functional assays demonstrated that whereas all PTCH1 isoforms can inhibit the activity of SHH, only the PTCH1B isoform is capable of fully inhibiting Smoh activity. The results indicate that in tumour cells the PTCH1B promoter is specifically activated and importantly, that the N-terminal part of PTCH1 including exon 1B is required for full inhibition of Smoh signaling but not for physical interaction with Smoh.

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References

  • Gailani MR, Ståhle-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

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

  • Hahn H, Wicking C, Zaphiropoulos PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgård R, Chenevix-Trench G, Wainwright B, Bale AE . 1996b Cell 85: 841–851

  • Incardona JP, Lee JH, Robertson CP, Enga K, Kapur RP, Roelink H . 2000 Proc. Natl. Acad. Sci. USA 97: 12044–12049

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

  • Ingham PW, Nystedt S, Nakano Y, Brown W, Stark D, van den Heuvel M, Taylor AM . 2000 Curr. Biol. 10: 1315–1318

  • 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

  • Johnson RL, Milenkovic L, Scott MP . 2000 Molecular Cell 6: 467–478

  • Kogerman P, Grimm T, Kogerman L, Krause D, Unden AB, Sandstedt B, Toftgård R, Zaphiropoulos PG . 1999 Nat. Cell Biol. 1: 312–319

  • Martin V, Carrillo G, Torroja C, Guerrero I . 2001 Curr. Biol. 11: 601–607

  • McGavrey T, Maruta Y, Tomaszewski JE, Linnenbach AJ, Malkovicz SB . 1998 Oncogene 17: 1167–1172

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

  • Ruiz i Altaba A . 1997 Cell 90: 193–196

  • Stone DM, Hynes M, Armanini M, Swanson TA, Gu Q, Johnson RL, Scott MP, Pennica D, Goddard A, Phillips H, Noll M, Hooper JE, de Sauvage F, Rosenthal A . 1996 Nature 384: 129–134

  • Strutt H, Thomas C, Nakano Y, Stark D, Neave B, Taylor AM, Ingham PW . 2001 Curr. Biol. 11: 608–613

  • Unden AB, Zaphiropoulos PG, Bruce K, Toftgård R, Stahle-Backdahl M . 1997 Cancer Res. 57: 2336–2340

  • Vorechovsky I, Tingby O, Hartman M et al . 1997a Oncogene 15: 361–366

  • Vorechovsky I, Undén AB, Sandstedt B, Toftgård R, Ståhle-Bäckdahl M . 1997b Cancer Res. 57: 4677–4681

  • Wang XQ, Rothnagel JA . 2001 J. Biol. Chem. 276: 1311–1316

  • Wang Y, Newton DC, Robb GB, Kau C, Miller TL, Cheung AH, Hall AV, VanDamme S, Wilcox JA, Marsden PA . 1999 Proc. Natl. Acad. Sci. USA 96: 12150–12155

  • 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

  • Zaphiropoulos PG, Toftgård R . 1996 DNA Cell Biol. 15: 1049–1056

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Acknowledgements

We would like to thank Haruhiko Akiyama (Kyoto University) for mouse Smoh cDNA. This study was supported by grants from the Swedish Cancer Fund, Swedish Medical Research Council, Estonian Ministry of Education and Howard Hughes Medical Institute.

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Author notes

  1. Priit Kogerman, Darren Krause and Fahimeh Rahnama: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biosciences at Novum, Karolinska Institutet, Huddinge, Sweden

    Priit Kogerman, Darren Krause, Fahimeh Rahnama, Lembi Kogerman, Anne Birgitte Undén, Peter G Zaphiropoulos & Rune Toftgård

  2. Department of Molecular Genetics, National Institute of Chemical Physics and Biophysics and Gene Technology Center, Tallinn Technical University, Tallinn, Estonia

    Priit Kogerman & Lembi Kogerman

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  1. Priit Kogerman
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Correspondence to Rune Toftgård.

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Kogerman, P., Krause, D., Rahnama, F. et al. Alternative first exons of PTCH1 are differentially regulated in vivo and may confer different functions to the PTCH1 protein. Oncogene 21, 6007–6016 (2002). https://doi.org/10.1038/sj.onc.1205865

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