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The p53 pathway: positive and negative feedback loops

Abstract

The p53 pathway responds to stresses that can disrupt the fidelity of DNA replication and cell division. A stress signal is transmitted to the p53 protein by post-translational modifications. This results in the activation of the p53 protein as a transcription factor that initiates a program of cell cycle arrest, cellular senescence or apoptosis. The transcriptional network of p53-responsive genes produces proteins that interact with a large number of other signal transduction pathways in the cell and a number of positive and negative autoregulatory feedback loops act upon the p53 response. There are at least seven negative and three positive feedback loops described here, and of these, six act through the MDM-2 protein to regulate p53 activity. The p53 circuit communicates with the Wnt-beta-catenin, IGF-1-AKT, Rb-E2F, p38 MAP kinase, cyclin-cdk, p14/19 ARF pathways and the cyclin G-PP2A, and p73 gene products. There are at least three different ubiquitin ligases that can regulate p53 in an autoregulatory manner: MDM-2, Cop-1 and Pirh-2. The meaning of this redundancy and the relative activity of each of these feedback loops in different cell types or stages of development remains to be elucidated. The interconnections between signal transduction pathways will play a central role in our understanding of cancer.

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References

  • Appella E and Anderson CW . (2001). Eur. J. Biochem., 268, 2764–2772.

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

  • Bates S, Rowan S and Vousden KH . (1996). Oncogene, 13, 1103–1109.

  • Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R and Weissberg P . (1998). Science, 282, 290–293.

  • Bergamaschi D, Gasco M, Hiller L, Sullivan A, Syed N, Trigiante G, Yulug I, Merlano M, Numico G, Comino A, Attard M, Reelfs O, Gusterson B, Bell AK, Heath V, Tavassoli M, Farrell PJ, Smith P, Lu X and Crook T . (2003). Cancer Cell, 3, 387–402.

  • Blander G, Zalle N, Leal JF, Bar-Or RL, Yu CE and Oren M . (2000). FASEB J., 14, 2138–2140.

  • Blandino G, Levine AJ and Oren M . (1999). Oncogene, 18, 477–485.

  • Bullock AN, Henckel J and Fersht AR . (2000). Oncogene, 19, 1245–1256.

  • Colman MS, Afshari CA and Barrett JC . (2000). Mutat. Res., 462, 179–188.

  • Dai MS and Lu H . (2004). J. Biol. Chem., 279, 44475–44482.

  • Dai MS, Zeng SX, Jin Y, Sun XX, David L and Lu H . (2004). Mol. Cell. Biol., 24, 7654–7668.

  • Damalas A, Kahan S, Shtutman M, Ben-Ze’ev A and Oren M . (2001). EMBO J., 20, 4912–4922.

  • Datta A, Nag A, Pan W, Hay N, Gartel AL, Colamonici O, Mori Y and Raychaudhuri P . (2004). J. Biol. Chem., 279, 36698–36707.

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

  • de Vries A, Flores ER, Miranda B, Hsieh HM, van Oostrom CT, Sage J and Jacks T . (2002). Proc. Natl. Acad. Sci. USA, 99, 2948–2953.

  • Dittmer D, Pati S, Zambetti G, Chu S, Teresky AK, Moore M, Finlay C and Levine AJ . (1993). Nat. Genet., 4, 42–46.

  • Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P, O’Rourke K, Koeppen H and Dixit VM . (2004). Nature, 429, 86–92.

  • Elenbaas B, Dobbelstein M, Roth J, Shenk T and Levine AJ . (1996). Mol. Med., 2, 439–451.

  • Epstein CB, Attiyeh EF, Hobson DA, Silver AL, Broach JR and Levine AJ . (1998). Oncogene, 16, 2115–2122.

  • Erster S, Mihara M, Kim RH, Petrenko O and Moll UM . (2004). Mol. Cell. Biol., 24, 6728–6741.

  • Fiucci G, Beaucourt S, Duflaut D, Lespagnol A, Stumptner-Cuvelette P, Geant A, Buchwalter G, Tuynder M, Susini L, Lassalle JM, Wasylyk C, Wasylyk B, Oren M, Amson R and Teleman A . (2004). Proc. Natl. Acad. Sci. USA, 101, 3510–3515.

  • Freedman DA, Epstein CB, Roth JC and Levine AJ . (1997). Mol. Med., 3, 248–259.

  • Gaiddon C, Lokshin M, Ahn J, Zhang T and Prives C . (2001). Mol. Cell. Biol., 21, 1874–1887.

  • Giaccia AJ and Kastan MB . (1998). Genes Dev., 12, 2973–2983.

  • Gottlieb TM, Leal JF, Seger R, Taya Y and Oren M . (2002). Oncogene, 21, 1299–1303.

  • Grob TJ, Novak U, Maisse C, Barcaroli D, Luthi AU, Pirnia F, Hugli B, Graber HU, De Laurenzi V, Fey MF, Melino G and Tobler A . (2001). Cell Death Differ., 8, 1213–1223.

  • Gudkov AV and Komarova EA . (2003). Nat. Rev. Cancer, 3, 117–129.

  • Harms K, Nozell S and Chen X . (2004). Cell Mol. Life Sci., 61, 822–842.

  • Haupt Y, Rowan S, Shaulian E, Kazaz A, Vousden K and Oren M . (1997). Leukemia, 11 (Suppl 3), 337–339.

  • Hoh J, Jin S, Parrado T, Edington J, Levine AJ and Ott J . (2002). Proc. Natl. Acad. Sci. USA, 99, 8467–8472.

  • Honda R and Yasuda H . (1999). EMBO J., 18, 22–27.

  • Iliakis G, Wang Y, Guan J and Wang H . (2003). Oncogene, 22, 5834–5847.

  • Iwai A, Marusawa H, Matsuzawa SI, Fukushima T, Hijikata M, Reed JC, Shimotohno K and Chiba T . (2004). Oncogene, 23, 7593–7600.

  • Jin S and Levine AJ . (2001). J. Cell Sci., 114, 4139–4140.

  • Jones SN, Roe AE, Donehower LA and Bradley A . (1995). Nature, 378, 206–208.

  • Jost CA, Marin MC and Kaelin Jr WG . (1997). Nature, 389, 191–194.

  • Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X, Ferrara P, McKeon F and Caput D . (1997). Cell, 90, 809–819.

  • Kartasheva NN, Contente A, Lenz-Stoppler C, Roth J and Dobbelstein M . (2002). Oncogene, 21, 4715–4727.

  • Kern SE, Kinzler KW, Baker SJ, Nigro JM, Rotter V, Levine AJ, Friedman P, Prives C and Vogelstein B . (1991). Oncogene, 6, 131–136.

  • Kimura SH, Ikawa M, Ito A, Okabe M and Nojima H . (2001). Oncogene, 20, 3290–3300.

  • Klein C and Vassilev LT . (2004). Br. J. Cancer, 91, 1415–1419.

  • Komarova EA, Diatchenko L, Rokhlin OW, Hill JE, Wang ZJ, Krivokrysenko VI, Feinstein E and Gudkov AV . (1998). Oncogene, 17, 1089–1096.

  • Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ and Pavletich NP . (1996). Science, 274, 948–953.

  • Lahav G, Rosenfeld N, Sigal A, Geva-Zatorsky N, Levine AJ, Elowitz MB and Alon U . (2004). Nat. Genet., 36, 147–150.

  • Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R and Benchimol S . (2003). Cell, 112, 779–791.

  • Lev Bar-Or R, Maya R, Segel LA, Alon U, Levine AJ and Oren M . (2000). Proc. Natl. Acad. Sci. USA, 97, 11250–11255.

  • Lin J, Chen J, Elenbaas B and Levine AJ . (1994). Genes Dev., 8, 1235–1246.

  • Lohrum MA, Ludwig RL, Kubbutat MH, Hanlon M and Vousden KH . (2003). Cancer Cell, 3, 577–587.

  • Lotem J, Gal H, Kama R, Amariglio N, Rechavi G, Domany E, Sachs L and Givol D . (2003). Proc. Natl. Acad. Sci. USA, 100, 6718–6723.

  • Louria-Hayon I, Grossman T, Sionov RV, Alsheich O, Pandolfi PP and Haupt Y . (2003). J. Biol. Chem., 278, 33134–33141.

  • Lowe SW and Sherr CJ . (2003). Curr. Opin. Genet. Dev., 13, 77–83.

  • Malkin D, Li FP, Strong LC, Fraumeni Jr JF, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ and Tainsky MA . (1990). Science, 250, 1233–1238.

  • Marechal V, Elenbaas B, Piette J, Nicolas JC and Levine AJ . (1994). Mol. Cell. Biol., 14, 7414–7420.

  • 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, Cook T and Kalin Jr WG . (2000). Nat. Genet., 25, 47–54.

  • Montes de Oca Luna R, Wagner DS and Lozano G . (1995). Nature, 378, 203–206.

  • Mothersill C and Seymour CB . (2004). Nat. Rev. Cancer, 4, 158–164.

  • Nakamura Y . (2004). Cancer Sci., 95, 7–11.

  • Nishizaki M, Fujiwara T, Tanida T, Hizuta A, Nishimori H, Tokino T, Nakamura Y, Bouvet M, Roth JA and Tanaka N . (1999). Clin. Cancer Res., 5, 1015–1023.

  • Okamoto K and Beach D . (1994). EMBO J., 13, 4816–4822.

  • Okamoto K, Li H, Jensen MR, Zhang T, Taya Y, Thorgeirsson SS and Prives C . (2002). Mol. Cell, 9, 761–771.

  • Oren M . (2003). Cell Death Differ., 10, 431–442.

  • Overholtzer M, Rao PH, Favis R, Lu XY, Elowitz MB, Barany F, Ladanyi M, Gorlick R and Levine AJ . (2003). Proc. Natl. Acad. Sci. USA, 100, 11547–11552.

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

  • Rajendra R, Malegaonkar D, Pungaliya P, Marshall H, Rasheed Z, Brownell J, Liu LF, Lutzker S, Saleem A and Rubin EH . (2004). J. Biol. Chem., 279, 36440–36444.

  • Schuler M, Bossy-Wetzel E, Goldstein JC, Fitzgerald P and Green DR . (2000). J. Biol. Chem., 275, 7337–7342.

  • Scott ML, Fujita T, Liou HC, Nolan GP and Baltimore D . (1993). Genes Dev., 7, 1266–1276.

  • Shaulian E, Zauberman A, Ginsberg D and Oren M . (1992). Mol. Cell. Biol., 12, 5581–5592.

  • 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.

  • Sugimoto M, Kuo ML, Roussel MF and Sherr CJ . (2003). Mol. Cell, 11, 415–424.

  • Takekawa M, Adachi M, Nakahata A, Nakayama I, Itoh F, Tsukuda H, Taya Y and Imai K . (2000). EMBO J., 19, 6517–6526.

  • Vaziri H . (1997). Biochemistry (Mosc.), 62, 1306–1310.

  • Vogelstein B, Lane D and Levine AJ . (2000). Nature, 408, 307–310.

  • Wu X and Levine AJ . (1994). Proc. Natl. Acad. Sci. USA, 91, 3602–3606.

  • Xiao ZX, Chen J, Levine AJ, Modjtahedi N, Xing J, Sellers WR and Livingston DM . (1995). Nature, 375, 694–698.

  • Yamasaki L . (2003). Cancer Treat. Res., 115, 209–239.

  • Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V, Andrews NC, Caput D and McKeon F . (1998). Mol. Cell, 2, 305–316.

  • Yardley G, Zauberman A, Oren M and Jackson P . (1998). FEBS Lett., 430, 171–175.

  • Zauberman A, Lupo A and Oren M . (1995). Oncogene, 10, 2361–2366.

  • Zhang T and Prives C . (2001). J. Biol. Chem., 276, 29702–29710.

  • Zhang Y, Wolf GW, Bhat K, Jin A, Allio T, Burkhart WA and Xiong Y . (2003). Mol. Cell. Biol., 23, 8902–8912.

  • Zhu H, Wu L and Maki CG . (2003). J. Biol. Chem., 278, 49286–49292.

  • Zhu JW, DeRyckere D, Li FX, Wan YY and DeGregori J . (1999). Cell Growth Differ., 10, 829–838.

  • 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 thank Victor Jin and Diane DePiano for assistance with the figures. This work was supported by grants to AJL from the Breast Cancer Research Foundation and the NIH Program Project Grant # CA-87497.

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Correspondence to Arnold J Levine.

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Harris, S., Levine, A. The p53 pathway: positive and negative feedback loops. Oncogene 24, 2899–2908 (2005). https://doi.org/10.1038/sj.onc.1208615

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