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The p53 network in lung carcinogenesis

Oncogene volume 21, pages 6898–6907 (2002)Cite this article

Abstract

The p53 tumor suppressor gene lies at the crossroads of multiple cellular response pathways that control a cell's fate in response to endogenous or exogenous stresses. Positive and negative regulatory loops both upstream and downstream of p53 cooperate to finely tune its functions as a transcription factor, a DNA damage sensor, and possibly, a protein-assembly scaffold. Through this plethora of activities, p53 is a major determinant of cell survival and a safeguard against genetic instability. Functional inactivation of p53 pathways through genetic and epigenetic events affecting the p53 gene itself and/or its interacting partners occur with a high frequency in lung cancer. The p53 mutational spectrum provides molecular evidence of the etiology of lung cancer and supports abundant epidemiological data indicating the role of tobacco smoke in the causation of this disease.

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References

  • Agami R, Blandino G, Oren M, Shaul Y . 1999 Nature 399: 809–813

  • Appella E, Anderson CW . 2001 Eur. J. Biochem. 268: 2764–2772

  • Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH . 1998 Nature 395: 124–125

  • Bennett WP, Colby TV, Vahakangas KH, Soini Y, Takeshima Y, Metcalf RA, Welsh JA, Borkowski A, Jones R, Trump BE, Lane CP, Travis WD, Samet JM, Harris CC . 1993 Cancer Res. 53: 4817–4822

  • Bertrand P, Rouillard D, Boulet A, Levalois C, Soussi T, Lopez BS . 1997 Oncogene 14: 1117–1122

  • Buchhop S, Gibson MK, Wang XW, Wagner P, Sturzbecher HW, Harris CC . 1997 Nucleic Acids Res. 25: 3868–3874

  • Chin L, Pomerantz J, DePinho RA . 1998 Trends Biochem. Sci. 23: 291–296

  • Cho Y, Gorina S, Jeffrey P, Pavletich NP . 1994 Science 265: 346–355

  • Cross SM, Sanchez CA, Morgan CA, Schimke MK, Ramel S, Idzerda RL, Raskind WH, Reid BJ . 1995 Science 267: 1353–1356

  • D'Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S, Gostissa M, Coen S, Marchetti A, Del Sal G, Piaggio G, Fanciulli M, Appella E, Soddu S . 2002 Nat. Cell Biol. 4: 11–19

  • DeMarini DM, Landi S, Tian D, Hanley NM, Li X, Hu F, Roop BC, Mass MJ, Keohavong P, Gao W, Olivier M, Hainaut P, Mumford JL . 2001 Cancer Res. 61: 6679–6681

  • Denissenko MF, Pao A, Tang M, Pfeifer GP . 1996 Science 274: 430–432

  • Di Como CJ, Gaiddon C, Prives C . 1999 Mol. Cell. Biol. 19: 1438–1449

  • Di Leonardo A, Linke SP, Clarkin K, Wahl GM . 1994 Genes Dev. 8: 2540–2551

  • Di Leonardo A, Khan SH, Linke SP, Greco V, Seidita G, Wahl GM . 1997 Cancer Res. 57: 1013–1019

  • Dudenhoffer C, Kurth M, Janus F, Deppert W, Wiesmuller L . 1999 Oncogene 18: 5773–5784

  • El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B . 1993 Cell 75: 817–825

  • Eymin B, Karayan L, Seite P, Brambilla C, Brambilla E, Larsen CJ, Gazzeri S . 2001a Oncogene 10: 1033–1041

  • Eymin B, Gazzeri S, Brambilla C, Brambilla E . 2001b Oncogene 20: 1678–1687

  • Fan R, Wu MT, Miller D, Wain JC, Kelsey KT, Wiencke JK, Christiani DC . 2000 Cancer Epidemiol. Biomarkers Prev. 9: 1037–1042

  • Flores ER, Tsai KY, Crowley D, Sengupta S, Yang A, McKeon F, Jacks T . 2002 Nature 416: 560–564

  • Ford JM, Hanawalt PC . 1995 Proc. Natl. Acad. Sci. USA 92: 8876–8880

  • Garkavtsev I, Riabowol K . 1997 Mol. Cell. Biol. 17: 2014–2019

  • Gazzeri S, Della VV, Chaussade L, Brambilla C, Larsen CJ, Brambilla E . 1998 Cancer Res. 58: 3926–3931

  • Gebow D, Miselis N, Liber HL . 2000 Mol. Cell. Biol. 20: 4028–4035

  • Goldman R, Enewold L, Pellizzari E, Beach JB, Bowman ED, Krishnan SS, Shields PG . 2001 Cancer Res. 61: 6367–6371

  • Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin Jr WG, Levrero M, Wang JY . 1999 Nature 399: 806–809

  • Graeber TG, Peterson JF, Tsai M, Monica K, Fornace Jr AJ, Giaccia AJ . 1994 Mol. Cell. Biol. 14: 6264–6277

  • Hagiwara K, McMenamin MG, Miura K, Harris CC . 1999 Cancer Res. 59: 4165–4169

  • Hainaut P, Pfeifer GP . 2001 Carcinogenesis 22: 367–374

  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ . 1993 Cell 75: 805–816

  • Harris CC, Genta VM, Frank AL, Kaufman DG, Barrett LA, McDowell EM, Trump BF . 1974 Nature 252: 68–69

  • Haupt Y, Maya R, Kazaz A, Oren M . 1997 Nature 387: 296–299

  • Hecht SS . 1999 J. Natl. Cancer Inst. 91: 1194–1210

  • Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S, Kinzler KW, Vogelstein B . 1997 Molec. Cell 1: 3–11

  • Hernandez-Boussard TM, Hainaut P . 1998 Environ. Health Perspect. 106: 385–391

  • Hibi K, Trink B, Patturajan M, Westra WH, Caballero OL, Hill DE, Ratovitski EA, Jen J, Sidransky D . 2000 Proc. Natl. Acad. Sci. USA 97: 5462–5467

  • Hofmann TG, Moller A, Sirma H, Zentgraf H, Taya Y, Droge W, Will H, Schmitz ML . 2002 Nat. Cell. Biol. 4: 1–10

  • Hollstein M, Sidransky D, Vogelstein B, Harris CC . 1991 Science 253: 49–53

  • Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T, Hovig E, Smith-Sorensen B, Montesano R, Harris CC . 1994 Nucl. Acids Res. 22: 3547–3551

  • Honma M, Zhang LS, Hayashi M, Takeshita K, Nakagawa Y, Tanaka N, Sofuni T . 1997 Mol. Cell. Biol. 17: 4774–4781

  • Hupp TR, Meek DW, Midgley CA, Lane DP . 1992 Cell 71: 875–886

  • Hussain SP, Harris CC . 1998 Cancer Res. 58: 4023–4037

  • Hussain SP, Amstad P, Raja K, Sawyer M, Hofseth LJ, Shields PG, Hewer A, Phillips DH, Ryberg D, Haugen A, Harris CC . 2001 Cancer Res. 61: 6350–6355

  • Hwang BJ, Ford JM, Hanawalt PC, Chu G . 1999 Proc. Natl. Acad. Sci. USA 96: 424–428

  • Iizasa T, Momiki S, Bauer B, Caamano J, Metcalf R, Lechner J, Harris CC, Klein-Szanto AJ . 1993 Carcinogenesis 14: 1789–1794

  • International Agency on the Research of Cancer. 1986 IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: Tobacco Smoking Lyon: IARC

  • Irwin M, Marin MC, Phillips AC, Seelan RS, Smith DI, Liu W, Flores ER, Tsai KY, Jacks T, Vousden KH, Kaelin Jr WG . 2000 Nature 407: 645–648

  • Irwin MS, Kaelin WG . 2001 Cell Growth Differ. 12: 337–349

  • Itahana K, Dimri G, Campisi J . 2001 Eur. J. Biochem. 268: 2784–2791

  • Jayaraman J, Prives C . 1995 Cell 81: 1021–1029

  • Jeffrey AM, Weinstein IB, Jennette KW, Grzeskowiak K, Nakanishi K, Harvey RG, Autrup H, Harris CC . 1977 Nature 269: 348–350

  • Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ . 1998 Proc. Natl. Acad. Sci. USA 95: 8292–8297

  • Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW . 1991 Cancer Res. 51: 6304–6311

  • Klein-Szanto AJ, Iizasa T, Momiki S, Garcia-Palazzo I, Caamano J, Metcalf R, Welsh J, Harris CC . 1992 Proc. Natl. Acad. Sci. USA 89: 6693–6697

  • Kubbutat MH, Jones SN, Vousden KH . 1997 Nature 387: 299–303

  • Lee S, Elenbaas B, Levine A, Griffith J . 1995 Cell 81: 1013–1020

  • Linke SP, Clarkin KC, Di Leonardo A, Tsou A, Wahl GM . 1996 Genes Dev. 10: 934–947

  • Liu G, Miller DP, Zhou W, Thurston SW, Fan R, Xu LL, Lynch TJ, Wain JC, Su L, Christiani DC . 2001 Cancer Res. 61: 8718–8722

  • Mai M, Yokomizo A, Qian C, Yang P, Tindall D, Smith DI, Liu W . 1998 Cancer Res. 58: 2347–2349

  • Marchetti A, Buttitta F, Pellegrini S, Merlo G, Chella A, Angeletti CA, Bevilacqua G . 1995 Diagn. Mol. Pathol. 4: 93–97

  • Mariatos G, Gorgoulis VG, Kotsinas A, Zacharatos P, Kokotas S, Yannoukakos D, Kittas C . 2000 Mutat. Res. 456: 59–63

  • Marin MC, Jost CA, Brooks LA, Irwin MS, O'Nions J, Tidy JA, James N, McGregor JM, Harwood CA, Yulug IG, Vousden KH, Allday MJ, Gusterson B, Ikawa S, Hinds PW, Crook T, Kaelin Jr WG . 2000 Nat. Genet. 25: 47–54

  • Mekeel KL, Tang W, Kachnic LA, Luo CM, DeFrank JS, Powell SN . 1997 Oncogene 14: 1847–1857

  • Miyashita T, Reed JC . 1995 Cell 80: 293–299

  • Moroni MC, Hickman ES, Denchi EL, Caprara G, Colli E, Cecconi F, Muller H, Helin K . 2001 Nat. Cell Biol. 3: 552–558

  • Nicholson SA, Okby NT, Khan MA, Welsh JA, McMenamin MG, Travis WD, Jett JR, Tazelaar HD, Trastek V, Pairolero PC, Corn PG, Herman JG, Liotta LA, Caporaso NE, Harris CC . 2001 Cancer Res. 61: 5636–5643

  • Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P, Glover T, Collins FS, Weston A, Modali R, Harris CC, Vogelstein B . 1989 Nature 342: 705–708

  • Nigro JM, Aldape KD, Hess SM, Tlsty TD . 1997 Cancer Res. 57: 3635–3639

  • Offer H, Wolkowicz R, Matas D, Blumenstein S, Livneh Z, Rotter V . 1999 FEBS Lett. 450: 197–204

  • Oren M . 1999 J. Biol. Chem. 274: 36031–36034

  • Ouchi T, Monteiro AN, August A, Aaronson SA, Hanafusa H . 1998 Proc. Natl. Acad. Sci. USA 95: 2302–2306

  • Palmero I, Pantoja C, Serrano M . 1998 Nature 395: 125–126

  • Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, Higashimoto Y, Appella E, Minucci S, Pandolfi PP, Pelicci PG . 2000 Nature 406: 207–210

  • Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B . 1997 Nature 389: 300–305

  • Prives C, Manley JL . 2001 Cell 107: 815–818

  • Prives C, Hall PA . 1999 J. Pathol. 187: 112–126

  • Robles AI, Bemmels NA, Foraker AB, Harris CC . 2001 Cancer Res. 61: 6660–6664

  • Robles AI, Harris CC . 2001 Acta Oncol. 40: 696–701

  • Rodin SN, Rodin AS . 2000 Proc. Natl. Acad. Sci. USA 97: 12244–12249

  • Saintigny Y, Rouillard D, Chaput B, Soussi T, Lopez BS . 1999 Oncogene 18: 3553–3563

  • Sanchez-Cespedes M, Reed AL, Buta M, Wu L, Westra WH, Herman JG, Yang SC, Jen J, Sidransky D . 1999 Oncogene 18: 5843–5849

  • Sherr CJ . 2000 Cancer Res. 60: 3689–3695

  • Sherr CJ . 2001 Nat. Rev. Mol. Cell. Biol. 2: 731–737

  • Sigal A, Rotter V . 2000 Cancer Res. 60: 6788–6793

  • Smith ML, Ford JM, Hollander MC, Bortnick RA, Amundson SA, Seo YR, Deng CX, Hanawalt PC, Fornace Jr AJ . 2000a Mol. Cell. Biol. 20: 3705–3714

  • Smith LE, Denissenko MF, Bennett WP, Li H, Amin S, Tang M, Pfeifer GP . 2000b J. Natl. Cancer Inst. 92: 803–811

  • Sozzi G, Miozzo M, Donghi R, Pilotti S, Cariani CT, Pastorino U, Della Porta G, Pierotti MA . 1992 Cancer Res. 52: 6079–6082

  • Spillare EA, Robles AI, Wang XW, Shen JC, Schellenberg GD, Harris CC . 1999 Genes Dev. 13: 1355–1360

  • Storey A, Thomas M, Kalita A, Harwood C, Gardiol D, Mantovani F, Breuer J, Leigh IM, Matlashewski G, Banks L . 1998 Nature 393: 229–234

  • Strano S, Munarriz E, Rossi M, Cristofanelli B, Shaul Y, Castagnoli L, Levine AJ, Sacchi A, Cesareni G, Oren M, Blandino G . 2000 J. Biol. Chem. 275: 29503–29512

  • Sturzbecher H-W, Donzelmann B, Henning W, Knippschild U, Buchhop S . 1996 EMBO J. 15: 1992–2002

  • Sundaresan V, Ganly P, Hasleton P, Rudd R, Sinha G, Bleehen NM, Rabbitts P . 1992 Oncogene 7: 1989–1997

  • Takahashi T, Nau MM, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, Levitt M, Pass H, Gazdar AF, Minna JD . 1989 Science 246: 491–494

  • Takeshima Y, Seyama T, Bennett WP, Akiyama M, Tokuoka S, Inai K, Mabuchi K, Land CE, Harris CC . 1993 Lancet 342: 1520–1521

  • Thomas M, Kalita A, Labrecque S, Pim D, Banks L, Matlashewski G . 1999 Mol. Cell. Biol. 19: 1092–1100

  • Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Hee PS, Thompson T, Karsenty G, Bradley A, Donehower LA . 2002 Nature 415: 45–53

  • Vahakangas KH, Samet JM, Metcalf RA, Welsh JA, Bennett WP, Lane DP, Harris CC . 1992 Lancet 339: 576–580

  • Vahakangas KH, Bennett WP, Castren K, Welsh JA, Khan MA, Blomeke B, Alavanja MC, Harris CC . 2001 Cancer Res. 61: 4350–4356

  • Venot C, Maratrat M, Dureuil C, Conseiller E, Bracco L, Debussche L . 1998 EMBO J. 17: 4668–4679

  • Vogelstein B, Lane D, Levine AJ . 2000 Nature 408: 307–310

  • Wahl GM, Carr AM . 2001 Nat. Cell Biol. 3: E277–E286

  • Walker KK, Levine AJ . 1996 Proc. Natl. Acad. Sci. USA 93: 15335–15340

  • Wang XW, Yeh H, Schaeffer L, Roy R, Moncollin V, Egly JM, Wang Z, Freidberg EC, Evans MK, Taffe BG, Bohr VA, Weeda G, Hoeijmakers JH, Forrester K, Harris CC . 1995 Nat. Genet. 10: 188–195

  • Wang XW, Vermeulen W, Coursen JD, Gibson M, Lupold SE, Forrester K, Xu G, Elmore L, Yeh H, Hoeijmakers JHJ, Harris CC . 1996 Genes Dev. 10: 1219–1232

  • Wang XW, Tseng A, Ellis NA, Spillare EA, Linke SP, Robles AI, Seker H, Yang Q, Hu P, Beresten S, Bemmels NA, Garfield S, Harris CC . 2001 J. Biol. Chem. 276: 32948–32955

  • Weber JD, Kuo ML, Bothner B, DiGiammarino EL, Kriwacki RW, Roussel MF, Sherr CJ . 2000a Mol. Cell. Biol. 20: 2517–2528

  • Weber JD, Jeffers JR, Rehg JE, Randle D, Lozano G, Roussel MF, Sherr CJ, Zambetti GP . 2000b Genes Dev. 14: 2358–2365

  • Weston A, Perrin LS, Forrester K, Hoover RN, Trump BF, Harris CC, Caporaso NE . 1992 CEBP 1: 481–483

  • Weston A, Bowman ED, Shields PG, Trivers GE, Poirier MC, Santella RM, Manchester DK . 1993 Environ. Health Perspect. 99: 257–259

  • Wiencke JK, Thurston SW, Kelsey KT, Varkonyi A, Wain JC, Mark EJ, Christiani DC . 1999 J. Natl. Cancer Inst. 91: 614–619

  • Wiesmuller L, Cammenga J, Deppert WW . 1996 J. Virol. 70: 737–744

  • Wistuba II, Gazdar AF, Minna JD . 2001 Semin. Oncol. 28: 3–13

  • Wolf P, Hu YC, Doffek K, Sidransky D, Ahrendt SA . 2001 Cancer Res. 61: 8113–8117

  • Wu GS, Burns TF, McDonald III ER, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G, El-Deiry WS . 1997 Nat. Genet. 17: 141–143

  • Yoon JH, Smith LE, Feng Z, Tang M, Lee CS, Pfeifer GP . 2001 Cancer Res. 61: 7110–7117

  • Yoshikawa H, Nagashima M, Khan MA, McMenamin MG, Hagiwara K, Harris CC . 1999 Oncogene 18: 3415–3421

  • Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang YY, Lu H, Kharbanda S, Weichselbaum R, Kufe D . 1999 Nature 399: 814–817

  • Zhou J, Ahn J, Wilson SH, Prives C . 2001 EMBO J. 20: 914–923

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Acknowledgements

We thank Judith Welsh for extraction and analysis of data from the IARC p53 database, Dr Pierre Hainaut for helpful comments, Karen McPherson for bibliographic support, and Dorothea Dudek for editorial assistance.

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  1. Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, Maryland, USA

    Ana I Robles, Steven P Linke & Curtis C Harris

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Robles, A., Linke, S. & Harris, C. The p53 network in lung carcinogenesis. Oncogene 21, 6898–6907 (2002). https://doi.org/10.1038/sj.onc.1205563

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