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Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization

Oncogene volume 19, pages 2978–2985 (2000)Cite this article

Abstract

The INK4a/ARF locus encodes two distinct tumour suppressors, p16INK4a and p14ARF, that regulate cell cycle progression via the pRB and p53 pathways, respectively. The ARF protein inhibits hdm2 activity, leading to the stabilization of the p53 tumour suppressor and cell cycle inhibition. The amino-terminal domain of human p14ARF and of the mouse homologue, p19ARF, is sufficient for these effects. This domain is also sufficient for the nucleolar localization of the mouse ARF protein. In contrast, we show that the human ARF protein requires two arginine rich domains, one in the amino- and the other in the carboxy-terminus, for nucleolar targeting. The amino-terminal nucleolar-targeting domain of p14ARF is also important for ARF-hdm2 binding and cell cycle inhibition. The carboxy-terminal p14ARF nucleolar localization domain lies within the shared INK4a/ARF exon 2, and is mutated in a small number of melanoma-prone kindreds. The INK4a/ARF exon2-mutations could affect the function of both the p16INK4a and p14ARF tumour suppressors.

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References

  • Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Voudsen KH, Pantoja C and Serrano M . 1998 Nature 395: 124–125

  • Burd CG and Dreyfuss G . 1994 Science 265: 615–620

  • Byeon I-JL, Li J, Ericson K, Selby TL, Tevelev A, Kim H-J, O'Maille P and Tsai M-D . 1998 Mol Cell 1: 421–431

  • Cattoretti G, Becker MHG, Key G, Duchrow M, Schlüter C, Galle J and Gerdes J . 1992 J Pathol 168: 357–363

  • de Stanchina E, McCurrach ME, Zindy F, Shieh S-Y, Ferbeyre G, Samuelson AV, Prives C, Roussel MF, Sherr CJ and Lowe SW . 1998 Genes Dev 12: 2434–2442

  • FitzGerald MG, Harkin DP, Silva-Arrieta S, MacDonald DJ, Lucchina LC, Unsal H, O'Neill E, Koh J, Finkelstein DM, Isselbacher KJ, Sober AJ and Haber DA . 1996 Proc Natl Acad Sci USA 93: 8541–8545

  • Fuchs SY, Adler V, Buschmann T, Wu X and Ronai Z . 1998 Oncogene 17: 2543–2547

  • Harland M, Meloni R, Gruis N, Pinney E, Brookes S, Spurr NK, Frischauf AM, Bataille V, Peters G, Cuzick J, Selby P, Bishop DT and Bishop JN . 1997 Hum Mol Genet 6: 2061–2067

  • Henderson BR and Percipalle P . 1997 J Mol Biol 274: 693–707

  • Holland EA, Schmid H, Kefford RF and Mann GJ . 1999 Genes Chrom Cancer 25: 1–10

  • Honda R, Tanaka H and Yasuda H . 1997 FEBS Lett 420: 25–27

  • Honda R and Yasuda H . 1999 EMBO J 18: 22–27

  • Hussussian CJ, Struewing JP, Goldstein AM, Higgins PAT, Ally DS, Sheahan MD, Clark WH, Jr, Tucker MA and Dracopoli NC . 1994 Nature Genet 8: 15–21

  • Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, Hussey C, Tran T, Miki Y, Weaver-Feldhaus J, McClure M, Aitken JF, Anderson DE, Bergman W, Frants R, Goldgar DE, Green A, MacLennan R, Martin NG, Meyer LJ, Youl P, Zone JJ, Skolnick MH and Cannon-Albright LA . 1994 Nature Genet 8: 23–26

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

  • Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G and Sherr CJ . 1997 Cell 91: 649–659

  • Kefford RF, Newton Bishop JA, Bergman W and Tucker MA . 1999 J Clin Oncol 17: 3245–3251

  • Lain S, Midgley C, Sparks A, Lane EB and Lane DP . 1999 Exp Cell Res 248: 457–472

  • Lee JY, Dong SM, Shin MS, Kim SY, Lee SH, Kang SJ, Lee JD, Kim CS, Kim SH and Yoo NJ . 1997 Biochem Biophys Res Commun 237: 667–672

  • Momand J, Zambetti GP, Olson DC, George D and Levine AJ . 1992 Cell 69: 1237–1245

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

  • Parry D and Peters G . 1996 Mol Cell Biol 16: 3844–3852

  • Piccinin S, Doglioni C, Maestro R, Vukosavljevic T, Gasparotto D, D'Orazi C and Boiocchi M . 1997 Int J Cancer 74: 26–30

  • Platz A, Hansson J, Mansson-Brahme E, Lagerlöf B, Linder S, Lundqvist E, Sevigny P, Inganas M and Ringborg U . 1997 J Nat Cancer Inst 89: 697–702

  • Pomerantz J, Schreiber-Agus N, Liégeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee H-W, Cordon-Cardo C and DePinho RA . 1998 Cell 92: 713–723

  • Quelle DE, Cheng M, Ashmum RA and Sherr CJ . 1997 Proc Natl Acad Sci USA 94: 669–673

  • Quelle DE, Zindy F, Ashmum RA and Sherr CJ . 1995 Cell 83: 993–1000

  • Ranade K, Hussussian CJ, Sirkosi RS, Varmus HE, Goldstein AM, Tucker MA, Serrano M, Hannon GJ, Beach D and Dracopoli NC . 1995 Nature Genet 10: 114–116

  • Reymond A and Brent R . 1995 Oncogene 11: 1173–1178

  • Rizos H, Becker TM, Holland EA, Kefford RF and Mann GJ . 1997 Oncogene 15: 515–523

  • Rizos H, Darmanian AP, Indsto JO, Shannon JA, Kefford RF and Mann GJ . 1999 Melanoma Res 9: 10–19

  • Roth J, Dobbelstein M, Freedman DA, Shenk T and Levine AJ . 1998 EMBO J 17: 554–564

  • Serrano M, Hannon GJ and Beach D . 1993 Nature 366: 704–707

  • Serrano M, Lee H-W, Chin L, Cordon-Cardo C, Beach D and DePinho RA . 1996 Cell 85: 27–37

  • Sharpless NE and DePinho RA . 1999 Curr Opin Genet Dev 9: 22–30

  • Soufir N, Avril M-F, Chompret A, Demenais F, Bombled J, Spatz A, Stoppa-Lyonnet D, Group the French Familial Melanoma Study Group, Bénard J and Bressac-de Paillerets B . 1998 Hum Mol Genet 7: 209–216

  • Stommel JM, Marchenko ND, Jimenez GS, Moll UM, Hope TJ and Wahl GM . 1999 EMBO J 18: 1660–1672

  • Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH and Peters G . 1998 EMBO J 17: 5001–5014

  • Tao W and Levine AJ . 1999 Proc Natl Acad Sci USA 96: 3077–3080

  • Walker GJ, Hussussian CJ, Flores JF, Glendening JM, Haluska FG, Dracopoli NC, Hayward NK and Fountain JW . 1995 Hum Mol Genet 4: 1845–1852

  • Weber JD, Taylor LJ, Roussel MF, Sherr CJ and Bar-Sagi D . 1999 Nature Cell Biol 1: 20–27

  • Zhang Y and Xiong Y . 1999 Molec Cell 3: 579–591

  • Zhang Y, Xiong Y and Yarbrough WG . 1998 Cell 92: 725–734

  • Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ and Roussel MF . 1998 Genes Dev 12: 2424–2433

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Acknowledgements

We are grateful to Mary Sartor and Patricia Mote for expert technical assistance and Dr Beric Henderson for critical reading of this manuscript. We thank Dr Tom Shenk for supplying the pCMVEGFP-spectrin plasmid, Dr Eiji Hara for supplying the pCMV-hdm2 plasmid and Dr M Yoshida for supplying leptomycin B. This work was supported by the National Health and Medical Research Council, the NSW Cancer Council, the Leo and Jenny Leukemia and Cancer Foundation, the Melanoma Foundation of the University of Sydney and the NSW Health Department.

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  1. Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, Westmead NSW 2145, Australia

    H Rizos, A P Darmanian, G J Mann & R F Kefford

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  1. H Rizos
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  2. A P Darmanian
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Rizos, H., Darmanian, A., Mann, G. et al. Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization. Oncogene 19, 2978–2985 (2000). https://doi.org/10.1038/sj.onc.1203629

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