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  • Original Paper
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Human p14ARF-mediated cell cycle arrest strictly depends on intact p53 signaling pathways

Abstract

The tumor suppressor ARF is transcribed from the INK4a/ARF locus in partly overlapping reading frames with the CDK inhibitor p16Ink4a. ARF is able to antagonize the MDM2-mediated ubiquitination and degradation of p53, leading to either cell cycle arrest or apoptosis, depending on the cellular context. However, recent data point to additional p53-independent functions of mouse p19ARF. Little is known about the dependency of human p14ARF function on p53 and its downstream genes. Therefore, we analysed the mechanism of p14ARF-induced cell cycle arrest in several human cell types. Wild-type HCT116 colon carcinoma cells (p53+/+p21CIP1+/+ 14-3-3σ+/+), but not p53−/− counterparts, underwent G1 and G2 cell cycle arrest following infection with a p14ARF-adenovirus. In p21CIP1−/− cells, p14ARF did not induce G1 or G2 arrest, while 14-3-3σ−/− counterparts were mainly arrested in G1, pointing to essential roles of p21CIP1 in G1 and G2 arrest and cooperative roles of p21 and 14-3-3σ in ARF-mediated G2 arrest. Our data demonstrate a strict p53 and p21CIP1 dependency of p14ARF-induced cell cycle arrest in human cells.

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References

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

  • Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, Sedivy JM, Kinzler KW, Vogelstein B . 1998 Science 282: 1497–1501

  • Burri N, Shaw P, Bouzourene H, Sordat I, Sordat B, Gillet M, Schorderet D, Bosman FT, Chaubert P . 2001 Lab. Invest. 81: 217–229

  • Carnero A, Hudson JD, Price CM, Beach DH . 2000 Nat. Cell Biol. 2: 148–155

  • Chan TA, Hermeking H, Lengauer C, Kinzler KW, Vogelstein B . 1999 Nature 401: 616–620

  • Chin L, Merlino G, DePinho RA . 1998a Genes Dev. 12: 3467–3481

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

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

  • Eymin B, Karayan L, Seite P, Brambilla C, Brambilla E, Larsen CJ, Gazzeri S . 2001 Oncogene 20: 1033–1041

  • Funk JO, Waga S, Harry JB, Espling E, Stillman B, Galloway DA . 1997 Genes Dev. 11: 2090–2100

  • He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B . 1998 Proc. Natl. Acad. Sci. USA 95: 2509–2514

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

  • Herzinger T, Funk JO, Hillmer K, Eick D, Wolf DA, Kind P . 1995 Oncogene 11: 2051–2056

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

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

  • Korgaonkar C, Zhao L, Modestou M, Quelle DE . 2002 Mol. Cell Biol. 22: 196–206

  • Levine AJ . 1997 Cell 88: 323–331

  • Llanos S, Clark PA, Rowe J, Peters G . 2001 Nat. Cell Biol. 3: 445–452

  • McShea A, Samuel T, Eppel JT, Galloway DA, Funk JO . 2000 J. Biol. Chem. 275: 23181–23186

  • Modestou M, Puig-Antich V, Korgaonkar C, Eapen A, Quelle DE . 2001 Cancer Res. 61: 3145–3150

  • No D, Yao TP, Evans RM . 1996 Proc. Natl. Acad. Sci. USA 16: 3346–3351

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

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

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

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

  • Radfar A, Unnikrishnan I, Lee HW, DePinho RA, Rosenberg N . 1998 Proc. Natl. Acad. Sci. USA 95: 13194–13199

  • Samuel T, Weber HO, Rauch P, Verdoodt B, Eppel JT, McShea A, Hermeking H, Funk JO . 2001 J. Biol. Chem. 276: 45201–45206

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

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

  • Sherr CJ, Roberts JM . 1995 Genes Dev. 9: 1149–1163

  • Sherr CJ . 1998 Genes Dev. 12: 2984–2991

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

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

  • Vousden KH . 2000 Cell 103: 691–694

  • Waldman T, Kinzler KW, Vogelstein B . 1995 Cancer Res. 55: 5187–5190

  • Waldman T, Lengauer C, Kinzler KW, Vogelstein B . 1996 Nature 381: 713–716

  • Waldman T, Zhang Y, Dillehay L, Yu J, Kinzler K, Vogelstein B, Williams J . 1997 Nat. Med. 3: 1034–1036

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

  • Wei W, Hemmer RM, Sedivy JM . 2001 Mol. Biol. Cell 21: 6748–6757

  • Weinberg RA . 1995 Cell 81: 323–330

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

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

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Acknowledgements

We thank Bert Vogelstein and Heiko Hermeking for cell lines and reagents; Denise Galloway and Jennifer Benanti for LXSN vectors; Karen Vousden for suggestions and discussion; Frank McCormick, Heiko Hermeking, Susanna Trapp, Andreas Baur, Berlinda Verdoodt, Tino Blazek, and Alexander Steinkasserer for comments; and Gerold Schuler for continuing support and encouragement. This work was supported by grants from the ELAN program of the University of Erlangen-Nuremberg and the Deutsche Forschungsgemeinschaft to JO Funk.

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Correspondence to Jens Oliver Funk.

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Weber, H., Samuel, T., Rauch, P. et al. Human p14ARF-mediated cell cycle arrest strictly depends on intact p53 signaling pathways. Oncogene 21, 3207–3212 (2002). https://doi.org/10.1038/sj.onc.1205429

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