Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Control of apoptosis by p53

Abstract

The p53 tumor suppressor acts to integrate multiple stress signals into a series of diverse antiproliferative responses. One of the most important p53 functions is its ability to activate apoptosis, and disruption of this process can promote tumor progression and chemoresistance. p53 apparently promotes apoptosis through transcription-dependent and -independent mechanisms that act in concert to ensure that the cell death program proceeds efficiently. Moreover, the apoptotic activity of p53 is tightly controlled, and is influenced by a series of quantitative and qualitative events that influence the outcome of p53 activation. Interestingly, other p53 family members can also promote apoptosis, either in parallel or in concert with p53. Although incomplete, our current understanding of p53 illustrates how apoptosis can be integrated into a larger tumor suppressor network controlled by different signals, environmental factors, and cell type. Understanding this network in more detail will provide insights into cancer and other diseases, and will identify strategies to improve their therapeutic treatment.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  • Alarcon-Vargas D and Ronai Z . (2002). Carcinogenesis, 23, 541–547.

  • Ambrosini G, Adida C and Altieri DC . (1997). Nat. Med., 3, 917–921.

  • Asher G, Lotem J, Cohen B, Sachs L and Shaul Y . (2001). Proc. Natl. Acad. Sci. USA, 98, 1188–1193.

  • Attardi LD and Jacks T . (1999). Cell. Mol. Life Sci., 55, 48–63.

  • Attardi LD, Lowe SW, Brugarolas J and Jacks T . (1996). EMBO J., 15, 3693–3701.

  • Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW and Jacks T . (2000). Genes Dev., 14, 704–718.

  • Aurelio ON, Kong XT, Gupta S and Stanbridge EJ . (2000). Mol. Cell Biol., 20, 770–778.

  • Bardeesy N, Beckwith JB and Pelletier J . (1995). Cancer Res., 55, 215–219.

  • Benard J, Douc-Rasy S and Ahomadegbe JC . (2003). Hum. Mutat., 21, 182–191.

  • 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.

  • Beroud C and Soussi T . (2003). Hum. Mutat., 21, 176–181.

  • Brodsky MH, Nordstrom W, Tsang G, Kwan E, Rubin GM and Abrams JM . (2000). Cell, 101, 103–113.

  • Caelles C, Helmberg A and Karin M . (1994). Nature, 370, 220–223.

  • Chang NS, Doherty J and Ensign A . (2003). J. Biol. Chem., 278, 9195–9202.

  • Chen X, Ko LJ, Jayaraman L and Prives C . (1996). Genes Dev., 10, 2438–2451.

  • Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML and Wyllie AH . (1993). Nature, 362, 849–852.

  • de Stanchina E and Lowe SW . (2002). Nat. Cell. Biol., 4, E275–E276.

  • 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.

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butel JS and Bradley A . (1992). Nature, 356, 215–221.

  • Dumont P, Leu JI, Della Pietra III AC, George DL and Murphy M . (2003). Nat. Genet., 33, 357–365.

  • Eischen CM, Roussel MF, Korsmeyer SJ and Cleveland JL . (2001). Mol. Cell. Biol., 21, 7653–7662.

  • Eischen CM, Weber JD, Roussel MF, Sherr CJ and Cleveland JL . (1999). Genes Dev., 13, 2658–2669.

  • el-Deiry WS . (1998). Semin. Cancer Biol., 8, 345–357.

  • Evan GI and Vousden KH . (2001). Nature, 411, 342–348.

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

  • Frantz S . (2001). Nat. Rev. Mol. Cell. Biol., 2, 872–873.

  • Fulda S, Scaffidi C, Pietsch T, Krammer PH, Peter ME and Debatin KM . (1998). Cell Death. Differ., 5, 884–893.

  • Green DR and Ferguson TA . (2001). Nat. Rev. Mol. Cell. Biol., 2, 917–924.

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

  • Guo Z, Yikang S, Yoshida H, Mak TW and Zacksenhaus E . (2001). Cancer Res., 61, 8395–8400.

  • Haupt Y, Rowan S, Shaulian E, Vousden KH and Oren M . (1995). Genes Dev., 9, 2170–2183.

  • Hoffman WH, Biade S, Zilfou JT, Chen J and Murphy M . (2002). J. Biol. Chem., 277, 3247–3257.

  • Hussain SP and Harris CC . (1998). Cancer Res., 58, 4023–4037.

  • Hwang PM, Bunz F, Yu J, Rago C, Chan TA, Murphy MP, Kelso GF, Smith RA, Kinzler KW and Vogelstein B . (2001). Nat. Med., 7, 1111–1117.

  • Ionov Y, Yamamoto H, Krajewski S, Reed JC and Perucho M . (2000). Proc. Natl. Acad. Sci. USA, 97, 10872–10877.

  • Irwin MS, Kondo K, Marin MC, Cheng LS, Hahn WC and Kaelin WG . (2003). Cancer Cell, 3, 403–410.

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

  • Jimenez GS, Nister M, Stommel JM, Beeche M, Barcarse EA, Zhang XQ, O'Gorman S and Wahl GM . (2000). Nat. Genet., 26, 37–43.

  • Jin S, Martinek S, Joo WS, Wortman JR, Mirkovic N, Sali A, Yandell MD, Pavletich NP, Young MW and Levine AJ . (2000). Proc. Natl. Acad. Sci. USA, 97, 7301–7306.

  • Johnstone RW, Ruefli AA and Lowe SW . (2002). Cell, 108, 153–164.

  • Juin P, Hunt A, Littlewood T, Griffiths B, Swigart LB, Korsmeyer S and Evan G . (2002). Mol. Cell. Biol., 22, 6158–6169.

  • Kannan K, Kaminski N, Rechavi G, Jakob-Hirsch J, Amariglio N and Givol D . (2001). Oncogene, 20, 3449–3455.

  • Kapoor M and Lozano G . (1998). Proc. Natl. Acad. Sci. USA, 95, 2834–2837.

  • Katoh I, Aisaki KI, Kurata SI, Ikawa S and Ikawa Y . (2000). Oncogene, 19, 3126–3130.

  • Knudson CM, Tung KS, Tourtellotte WG, Brown GA and Korsmeyer SJ . (1995). Science, 270, 96–99.

  • Ko LJ and Prives C . (1996). Genes Dev., 10, 1054–1072.

  • Kokontis JM, Wagner AJ, O'Leary M, Liao S and Hay N . (2001). Oncogene, 20, 659–668.

  • Komarova EA and Gudkov AV . (2001). Biochem. Pharmacol., 62, 657–667.

  • Koumenis C, Alarcon R, Hammond E, Sutphin P, Hoffman W, Murphy M, Derr J, Taya Y, Lowe SW, Kastan M and Giaccia A . (2001). Mol. Cell. Biol., 21, 1297–1310.

  • Kroemer G and Reed JC . (2000). Nat. Med., 6, 513–519.

  • Kuerbitz SJ, Plunkett BS, Walsh WV and Kastan MB . (1992). Proc. Natl. Acad. Sci. USA, 89, 7491–7495.

  • Lane DP . (1992). Nature, 358, 15–16.

  • Li LY, Luo X and Wang X . (2001). Nature, 412, 95–99.

  • Lin AW and Lowe SW . (2001). Proc. Natl. Acad. Sci. USA, 98, 5025–5030.

  • Lin Y, Ma W and Benchimol S . (2000). Nat. Genet., 26, 122–127.

  • Lissy NA, Davis PK, Irwin M, Kaelin WG and Dowdy SF . (2000). Nature, 407, 642–645.

  • Lowe SW and Lin AW . (2000). Carcinogenesis, 21, 485–495.

  • Lowe SW and Ruley HE . (1993). Genes Dev., 7, 535–545.

  • Lowe SW, Ruley HE, Jacks T and Housman DE . (1993a). Cell, 74, 957–967.

  • Lowe SW, Schmitt EM, Smith SW, Osborne BA and Jacks T . (1993b). Nature, 362, 847–849.

  • Lu H, Taya Y, Ikeda M and Levine AJ . (1998). Proc. Natl. Acad. Sci. USA, 95, 6399–6402.

  • Mack DH, Vartikar J, Pipas JM and Laimins LA . (1993). Nature, 363, 281–283.

  • MacLachlan TK and El-Deirg WS . (2002). Proc. Natl. Acad. Sci. USA, 99, 9992–9997.

  • Maecker HL, Koumenis C and Giaccia AJ . (2000). Cancer Res., 60, 4638–4644.

  • Marsden VS, O'Connor L, O'Reilly LA, Silke J, Metcalf D, Ekert PG, Huang DC, Cecconi F, Kuida K, Tomaselli KJ, Roy S, Nicholson DW, Vaux DL, Bouillet P, Adams JM and Strasser A . (2002). Nature, 419, 634–637.

  • Matsuda K, Yoshida K, Taya Y, Nakamura K, Nakamura Y and Arakawa H . (2002). Cancer Res., 62, 2883–2889.

  • Mattson MP, Duan W, Pedersen WA and Culmsee C . (2001). Apoptosis, 6, 69–81.

  • McCurrach ME, Connor TM, Knudson CM, Korsmeyer SJ and Lowe SW . (1997). Proc. Natl. Acad. Sci. USA, 94, 2345–2349.

  • Meek DW . (1999). Oncogene, 18, 7666–7675.

  • Meijerink JP, Mensink EJ, Wang K, Sedlak TW, Sloetjes AW, de Witte T, Waksman G and Korsmeyer SJ . (1998). Blood, 91, 2991–2997.

  • Melino G, De Laurenzi V and Vousden KH . (2002). Nat. Rev. Cancer, 2, 605–615.

  • Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P and Moll UM . (2003). Mol. Cell, 11, 577–590.

  • Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR and Bradley A . (1999). Nature, 398, 708–713.

  • Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B and Reed JC . (1994). Oncogene, 9, 1799–1805.

  • Moll UM, Erster S and Zaika A . (2001). Biochim. Biophys. Acta, 1552, 47–59.

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

  • Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M, Friedman SL, Galle PR, Stremmel W, Oren M and Krammer PH . (1998). J. Exp. Med., 188, 2033–2045.

  • Murphy M, Ahn J, Walker KK, Hoffman WH, Evans RM, Levine AJ and George DL . (1999). Genes Dev., 13, 2490–2501.

  • Nahle Z, Polakoff J, Davuluri RV, McCurrach ME, Jacobson MD, Narita M, Zhang MQ, Lazebnik Y, Bar-Sagi D and Lowe SW . (2002). Nat. Cell Biol., 4, 859–864.

  • Nakano K and Vousden KH . (2001). Mol. Cell, 7, 683–694.

  • Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T and Tanaka N . (2000a). Science, 288, 1053–1058.

  • Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y and Taya Y . (2000b). Cell, 102, 849–862.

  • Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M and Nakamura Y . (2001). Mol. Cell, 8, 85–94.

  • Ollmann M, Young LM, Di Como CJ, Karim F, Belvin M, Robertson S, Whittaker K, Demsky M, Fisher WW, Buchman A, Duyk G, Friedman L, Prives C and Kopczynski C . (2000). Cell, 101, 91–101.

  • Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, Roth JA, Deisseroth AB, Zhang WW, Kruzel E and Radinsky R . (1995). Mol. Cell. Biol., 15, 3032–3040.

  • Paramio JM, Segrelles C, Ruiz S, Martin-Caballero J, Page A, Martinez J, Serrano M and Jorcano JL . (2001). J. Biol. Chem., 276, 44203–44211.

  • Parant JM and Lozano G . (2003). Hum. Mutat., 21, 321–326.

  • Pelengaris S, Khan M and Evan G . (2002). Nat. Rev. Cancer, 2, 764–776.

  • Petak I, Tillman DM and Houghton JA . (2000). Clin. Cancer Res., 6, 4432–4441.

  • Peter ME and Krammer PH . (2003). Cell Death Differ., 10, 26–35.

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

  • Prives C and Hall PA . (1999). J. Pathol., 187, 112–126.

  • Prives C and Manley JL . (2001). Cell, 107, 815–818.

  • Ries S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T, McMahon M, Oren M and McCormick F . (2000). Cell, 103, 321–330.

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

  • Sax JK and el-Deiry WS . (2003). Cell Death Differ., 10, 413–417.

  • Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ and El-Deiry WS . (2002). Nat. Cell Biol., 4, 842–849.

  • Schmitt CA, Fridman JS, Yang M, Baranov E, Hoffman RM and Lowe SW . (2002a). Cancer Cell, 1, 289–298.

  • Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM and Lowe SW . (2002b). Cell, 109, 335–346.

  • Schmitt CA, McCurrach ME, de Stanchina E, Wallace-Brodeur RR and Lowe SW . (1999). Genes Dev., 13, 2670–2677.

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

  • Schumacher B, Hofmann K, Boulton S and Gartner A . (2001). Curr. Biol., 11, 1722–1727.

  • Seoane J, Le HV and Massague J . (2002). Nature, 419, 729–734.

  • Serrano M, Lin AW, McCurrach ME, Beach D and Lowe SW . (1997). Cell, 88, 593–602.

  • Shieh SY, Ikeda M, Taya Y and Prives C . (1997). Cell, 91, 325–334.

  • Soengas MS, Alarcon RM, Yoshida H, Giaccia AJ, Hakem R, Mak TW and Lowe SW . (1999). Science, 284, 156–159.

  • Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C and Lowe SW . (2001). Nature, 409, 207–211.

  • Soengas MS and Lowe SW . (2000). Nat. Genet., 26, 391–392.

  • Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S and Mak TW . (2001). Mol. Cell, 8, 317–325.

  • Stiewe T and Putzer BM . (2000). Nat. Genet., 26, 464–469.

  • Strasser A, Harris AW, Bath ML and Cory S . (1990). Nature, 348, 331–333.

  • Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T and Van Dyke T . (1994). Cell, 78, 703–711.

  • Tsujimoto Y . (2003). J. Cell. Physiol., 195, 158–167.

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

  • Vivanco I and Sawyers CL . (2002). Nat. Rev. Cancer, 2, 489–501.

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

  • Vousden KH and Lu X . (2002). Nat. Rev. Cancer, 2, 594–604.

  • Wagner AJ, Kokontis JM and Hay N . (1994). Genes Dev., 8, 2817–2830.

  • Wallace-Brodeur RR and Lowe SW . (1999). Cell. Mol. Life Sci., 55, 64–75.

  • Webley K, Bond JA, Jones CJ, Blaydes JP, Craig A, Hupp T and Wynford-Thomas D . (2000). Mol. Cell. Biol., 20, 2803–2808.

  • Woods D, Parry D, Cherwinski H, Bosch E, Lees E and McMahon M . (1997). Mol. Cell. Biol., 17, 5598–5611.

  • Wosik K, Antel J, Kuhlmann T, Bruck W, Massie B and Nalbantoglu J . (2003). J. Neurochem., 85, 635–644.

  • 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 and el-Deiry WS . (1997). Nat. Genet., 17, 141–143.

  • Yang A, Kaghad M, Caput D and McKeon F. . (2002). Trends Genet., 18, 90–95.

  • Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C and McKeon F . (1999). Nature, 398, 714–718.

  • Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, Vagner C, Bonnet H, Dikkes P, Sharpe A, McKeon F and Caput D . (2000). Nature, 404, 99–103.

  • Yin C, Knudson CM, Korsmeyer SJ and Van Dyke T . (1997). Nature, 385, 637–640.

  • Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A and Oren M . (1991). Nature, 352, 345–347.

  • Yu J, Wang Z, Kinzler KW, Vogelstein B and Zhang L . (2003). Proc. Natl. Acad. Sci. USA, 100, 1931–1936.

  • Yu J, Zhang L, Hwang PM, Rago C, Kinzler KW and Vogelstein B . (1999). Proc. Natl. Acad. Sci. USA, 96, 14517–14522.

  • Zhang CC, Yang JM, Bash-Babula J, White E, Murphy M, Levine AJ and Hait WN . (1999). Cancer Res., 59, 3663–3670.

  • Zhang CC, Yang JM, White E, Murphy M, Levine A and Hait WN . (1998). Oncogene, 16, 1617–1624.

  • Zhang L, Yu J, Park BH, Kinzler KW and Vogelstein B . (2000). Science, 290, 989–992.

  • Zhao R, Gish K, Murphy M, Yin Y, Notterman D, Hoffman WH, Tom E, Mack DH and Levine AJ . (2000). Genes Dev., 14, 981–993.

Download references

Acknowledgements

We thank M McCurrach for her help with this manuscript, M Soengas for critical review, and J Duffy for his help with graphic design. We also thank the Laurie Strauss Leukemia Foundation for their support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Scott W Lowe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fridman, J., Lowe, S. Control of apoptosis by p53. Oncogene 22, 9030–9040 (2003). https://doi.org/10.1038/sj.onc.1207116

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207116

Keywords

This article is cited by

Search

Quick links