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Functional evidence for a squamous cell carcinoma mortality gene(s) on human chromosome 4

Oncogene volume 21, pages 5135–5147 (2002)Cite this article

Abstract

Squamous cell carcinoma (SCC) immortality is associated with p53 and INK4A dysfunction, high levels of telomerase and loss of heterozygosity (LOH) of other chromosomes, including chromosome 4. To test for a functional cancer mortality gene on human chromosome 4 we introduced a complete or fragmented copy of the chromosome into SCC lines by microcell-mediated chromosome transfer (MMCT). Human chromosome 4 caused a delayed crisis, specifically in SCC lines with LOH on chromosome 4, but chromosomes 3, 6, 11 and 15 were without effect. The introduction of the telomerase reverse transcriptase into the target lines extended the average telomere terminal fragment length but did not affect the frequency of mortal hybrids following MMCT of chromosome 4. Furthermore, telomerase activity was still present in hybrids displaying the mortal phenotype. The MMCT of chromosomal fragments into BICR6 mapped the mortality gene to between the centromere and 4q23. Deletion analysis of the introduced chromosome in immortal segregants narrowed the candidate interval to 2.7 Mb spanning D4S423 and D4S1557. The results suggest the existence of a gene on human chromosome 4 whose dysfunction contributes to the continuous proliferation of SCC and that this gene operates independently from telomeres, p53 and INK4A.

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References

  • Adra CN, Donato JL, Badovinac R, Syed F, Kheraj R, Cai H, Moran C, Kolker MT, Turner H, Weremowicz S, Shirakawa T, Morton CC, Schnipper LE, Drews R . 2000 Genomics 69: 162–173

  • Arribas R, Risques RA, Gonzalez-Garcia I, Masramon L, Aiza G, Ribas M, Capella G, Peinado MA . 1999 Lab. Invest. 79: 111–122

  • Backsch C, Wagenbach N, Nonn M, Leistritz S, Stanbridge E, Schneider A, Durst M . 2001 Genes Chromosomes Cancer 31: 196–198

  • Ben-Arie N, McCall AE, Berkman S, Eichele G, Bellen HJ, Zoghbi HY . 1996 Hum. Mol. Genet. 5: 1207–1216

  • Bertram MJ, Berube NG, Hang-Swanson X, Ran Q, Leung JK, Bryce S, Spurgers K, Bick RJ, Baldini A, Ning Y, Clark LJ, Parkinson EK, Barrett JC, Smith JR, Pereira-Smith OM . 1999 Mol. Cell. Biol. 19: 1479–1485

  • Bluteau O, Beaudoin JC, Pasturaud P, Belghiti J, Franco D, Bioulac-Sage P, Laurent-Puig P, Zucman-Rossi J . 2002 Oncogene 21: 1225–1232

  • Bryce SD, Forsyth NR, Fitzsimmons SA, Clark LJ, Bertram MJ, Cuthbert AP, Newbold RF, Pereira-Smith OM, Parkinson EK . 1999 Cancer Res. 59: 2038–2040

  • Buetow KH, Murray JC, Israel JL, London WT, Smith M, Kew M, Blanquet V, Brechot C, Redeker A, Govindarajah S . 1989 Proc. Natl. Acad. Sci. USA 86: 8852–8856

  • Casey G, Plummer S, Hoeltge G, Scanlon D, Fasching C, Stanbridge EJ . 1993 Hum. Mol. Genet. 2: 1921–1927

  • Clark LJ, Edington K, Swan IR, McLay KA, Newlands WJ, Wills LC, Young HA, Johnston PW, Mitchell R, Robertson G, Soutar D, Mitchell R, Parkinson EK, Birnie GD . 1993 Br. J. Cancer 68: 617–620

  • Cottage A, Dowen S, Roberts I, Pett M, Coleman N, Stanley M . 2001 Genes Chromosomes Cancer 30: 72–79

  • Cuthbert AP, Trott DA, Ekong RM, Jezzard S, England NL, Themis M, Todd CM, Newbold RF . 1995 Cytogenet. Cell Genet. 71: 68–76

  • Edington KG, Loughran OP, Berry IJ, Parkinson EK . 1995 Mol. Carcinog. 13: 254–265

  • England NL, Cuthbert AP, Trott DA, Jezzard S, Nobori T, Carson DA, Newbold RF . 1996 Carcinogenesis 17: 1567–1575

  • Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A, Beijersbergen RL, Knoll JH, Meyerson M, Weinberg RA . 1999 Nat. Med. 5: 1164–1170

  • Hensler PJ, Annab LA, Barrett JC, Pereira-Smith OM . 1994 Mol. Cell. Biol. 14: 2291–2297

  • Hu N, Roth MJ, Polymeropolous M, Tang ZZ, Emmert-Buck MR, Wang QH, Goldstein AM, Feng SS, Dawsey SM, Ding T, Zhuang ZP, Han XY, Ried T, Giffen C, Taylor PR . 2000 Genes Chromosomes Cancer 27: 217–228

  • Hu W, Zuo J, De Jager PL, Heintz N . 1998 Genomics 47: 143–145

  • Kanaoka Y, Ago H, Inagaki E, Nanayama T, Miyano M, Kikuno R, Fujii Y, Eguchi N, Toh H, Urade Y, Hayaishi O . 1997 Cell 90: 1085–1095

  • Karlsson C, Stenman G, Vojta PJ, Bongcam-Rudloff E, Barrett JC, Westermark B, Paulsson Y . 1996 Cancer Res. 56: 241–245

  • Koi M, Johnson LA, Kalikin LM, Little PF, Nakamura Y, Feinberg AP . 1993 Science 260: 361–364

  • Lee YA, Stevens HP, Delaporte E, Wahn U, Reis A . 2000 Am. J. Hum. Genet. 66: 326–330

  • Loughran O, Clark LJ, Bond J, Baker A, Berry IJ, Edington KG, Ly IS, Simmons R, Haw R, Black DM, Newbold RF, Parkinson EK . 1997 Oncogene 14: 1955–1964

  • Lupton SD, Brunton LL, Kalberg VA, Overell RW . 1991 Mol. Cell. Biol. 11: 3374–3378

  • McGregor F, Wagner E, Felix D, Soutar D, Parkinson K, Harrison PR . 1997 Cancer Res. 57: 3886–3889

  • Mitra AB, Murty VV, Li RG, Pratap M, Luthra UK, Chaganti RS . 1994 Cancer Res. 54: 4481–4487

  • Ning Y, Weber JL, Killary AM, Ledbetter DH, Smith JR, Pereira-Smith OM . 1991 Proc. Natl. Acad. Sci. USA 88: 5635–5639

  • Ogata T, Ayusawa D, Namba M, Takahashi E, Oshimura M, Oishi M . 1993 Mol. Cell. Biol. 13: 6036–6043

  • Parkinson EK, Newbold RF, Keith WN . 1997 Eur. J. Cancer 33: 727–734

  • Pershouse MA, El-Naggar AK, Hurr K, Lin H, Yung WK, Steck PA . 1997 Oncogene 14: 369–373

  • Petersen I, Langreck H, Wolf G, Schwendel A, Psille R, Vogt P, Reichel MB, Ried T, Dietel M . 1997 Br. J. Cancer 75: 79–86

  • Rimessi P, Gualandi F, Morelli C, Trabanelli C, Wu Q, Possati L, Montesi M, Barrett JC, Barbanti-Brodano G . 1994 Oncogene 9: 3467–3474

  • Robertson GP, Furnari FB, Miele ME, Glendening MJ, Welch DR, Fountain JW, Lugo TG, Huang HJ, Cavenee WK . 1998 Proc. Natl. Acad. Sci. USA 95: 9418–9423

  • Rumpel CA, Powell SM, Moskaluk CA . 1999 Am. J. Pathol. 154: 1329–1334

  • Sandhu AK, Hubbard K, Kaur GP, Jha KK, Ozer HL, Athwal RS . 1994 Proc. Natl. Acad. Sci. USA 91: 5498–5502

  • Sandhu AK, Kaur GP, Reddy DE, Rane NS, Athwal RS . 1996 Oncogene 12: 247–252

  • Sasaki M, Honda T, Yamada H, Wake N, Barrett JC, Oshimura M . 1994 Cancer Res. 54: 6090–6093

  • Shah SI, Yip L, Greenberg B, Califano JA, Chow J, Eisenberger CF, Lee DJ, Sewell DA, Reed AL, Lango M, Jen J, Koch WM, Sidransky D . 2000 Arch. Otolaryngol. Head Neck Surg. 126: 1073–1076

  • Shimada Y, Saito A, Suzuki M, Takahashi E, Horie M . 1998 Cytogenet. Cell Genet. 83: 232–235

  • Snedecor GW, Cochrane WG . 1973 Statistical Methods Iowa: Iowa State University Press

    Google Scholar 

  • Soininen R, Schoor M, Henseling U, Tepe C, Kisters-Woike B, Rossant J, Gossler A . 1992 Mech. Dev. 39: 111–123

  • Stanton P, Richards S, Reeves J, Nikolic M, Edington K, Clark L, Robertson G, Souter D, Mitchell R, Hendler FJ, Cooke T, Parkinson EK, Ozanne B . 1994 Br. J. Cancer 70: 427–433

  • Stein GH . 1985 J. Cell Physiol. 125: 36–44

  • Tanner MM, Karhu RA, Nupponen NN, Borg A, Baldetorp B, Pejovic T, Ferno M, Killander D, Isola JJ . 1998 Am. J. Pathol. 153: 191–199

  • Terada Y, Imoto I, Nagai H, Suwa K, Momoi M, Tajiri T, Onda M, Inazawa J, Emi M . 2001 Am. J. Med. Genet. 103: 176–180

  • Uejima H, Mitsuya K, Kugoh H, Horikawa I, Oshimura M . 1995 Genes Chromosomes Cancer 14: 120–127

  • Vaziri H, Benchimol S . 1998 Curr. Biol. 8: 279–282

  • Virgin JB, Hurley PM, Nahhas FA, Bebchuk KG, Mohamed AN, Sakr WA, Bright RK, Cher ML . 1999 Prostate 41: 49–57

  • Wang XL, Uzawa K, Imai FL, Tanzawa H . 1999 Oncogene 18: 823–825

  • Wang XW, Lin X, Klein CB, Bhamra RK, Lee YW, Costa M . 1992 Carcinogenesis 13: 555–561

  • Zhu J, Wang H, Bishop JM, Blackburn EH . 1999 Proc. Natl. Acad. Sci. USA 96: 3723–3728

  • Zhu Z, Yao J, Johns T, Fu K, De Bie I, Macmillan C, Cuthbert AP, Newbold RF, Wang J, Chevrette M, Brown GK, Brown RM, Shoubridge EA . 1998 Nat. Genet. 20: 337–343

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Acknowledgements

The authors wish to thank Cancer Research UK and the Association for International Cancer Research for financial support and Professors John Wyke and Paul Harrison for critical review of the manuscript.

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Authors and Affiliations

  1. Beatson Institute for Cancer Research, CRC Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK

    Nicholas R Forsyth, Vivienne Morrison, Nicola J Craig, Sara A Fitzsimmons, Nighean I Barr, Hazel Ireland, Katrina E Gordon, Steven D Bryce & E Kenneth Parkinson

  2. The Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK

    Sally Dowen

  3. The Department Biological Sciences Brunel University, Uxbridge, Middlesex, UB8 3PH, UK

    Andrew P Cuthbert & Robert F Newbold

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  1. Nicholas R Forsyth
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  2. Vivienne Morrison
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Correspondence to E Kenneth Parkinson.

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Forsyth, N., Morrison, V., Craig, N. et al. Functional evidence for a squamous cell carcinoma mortality gene(s) on human chromosome 4. Oncogene 21, 5135–5147 (2002). https://doi.org/10.1038/sj.onc.1205688

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