Abstract
Over the years, p53 has been shown to sit at the centre of an increasingly complex web of incoming stress signals and outgoing effector pathways. The number and diversity of stress signals that lead to p53 activation illustrates the breadth of p53's remit – responding to a wide variety of potentially oncogenic insults to prevent tumour development. Interestingly, different stress signals can use different and independent pathways to activate p53, and there is some evidence that different stress signals can mediate different responses. How each of the responses to p53 contributes to inhibition of malignant progression is beginning to be clarified, with the hope that identification of responses that are key to tumour suppression will allow a more focused and effective search for new therapeutic targets. In this review, we will highlight some recently identified roles for p53 in tumour suppression, and discuss some of the numerous mechanisms through which p53 can be regulated and activated.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abida WM, Nikolaev A, Zhao W, Zhang W, Gu W . (2006). FBXO11 promotes the neddylation of p53 and inhibits its transcriptional activity. J Biol Chem [Epub ahead of print].
Adhikary S, Marinoni F, Hock A, Hulleman E, Popov N, Beier R et al. (2005). The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. Cell 123: 409–421.
Amsterdam A, Sadler KC, Lai K, Farrington S, Bronson RT, Lees JA et al. (2004). Many ribosomal protein genes are cancer genes in zebrafish. PLoS Biol 2: E139.
Andrews P, He YJ, Xiong Y . (2006). Cytoplasmic localized ubiquitin ligase cullin 7 binds to p53 and promotes cell growth by antagonizing p53 function. Oncogene 25: 4534–4548.
Asher G, Lotem J, Cohen B, Sachs L, Shaul Y . (2001). Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proc Natl Acad Sci USA 98: 1188–1193.
Asher G, Shaul Y . (2005). p53 proteasomal degradation: poly-ubiquitination is not the whole story. Cell Cycle 4: 1015–1018.
Banin S, Moyal L, Shieh S-Y, Taya Y, Anderson CW, Chessa L et al. (1998). Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281: 1674–1677.
Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K et al. (2005). DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434: 864–870.
Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R et al. (2006). TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126: 107–120.
Bensaad K, Vousden KH . (2005). Savior and slayer: the two faces of p53. Nat Med 11: 1278–1279.
Bhat KP, Itahana K, Jin A, Zhang Y . (2004). Essential role of ribosomal protein L11 in mediating growth inhibition-induced p53 activation. EMBO J 23: 2402–2412.
Bischof O, Schwamborn K, Martin N, Werner A, Sustmann C, Grosschedl R et al. (2006). The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis. Mol Cell 22: 783–794.
Bode AM, Dong Z . (2004). Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 4: 793–805.
Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC et al. (2004). A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119: 591–602.
Boyd SD, Tsai KY, Jacks T . (2000). An intact HDM2 RING-finger domain is required for nuclear exclusion of p53. Nature Cell Biol 2: 563–568.
Brady M, Vlatkovic N, Boyd MT . (2005). Regulation of p53 and MDM2 activity by MTBP. Mol Cell Biol 25: 545–553.
Budanov AV, Sablina AA, Feinstein E, Koonin EV, Chumakov PM . (2004). Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304: 596–600.
Bykov VJ, Wiman KG . (2003). Novel cancer therapy by reactivation of the p53 apoptosis pathway. Ann Med 35: 458–465.
Chen C, Sun X, Guo P, Dong XY, Sethi P, Cheng X et al. (2005a). Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells. J Biol Chem 280: 41553–41561.
Chen D, Kon N, Li M, Zhang W, Qin J, Gu W . (2005b). ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 121: 1071–1083.
Cheng TH, Cohen SN . (2007). Human MDM2 isoforms translated differentially on constitutive vs p53-regulated transcripts have distinct functions in the p53/MDM2 and TSG101/MDM2 feedback control loops. Mol Cell Biol 27: 111–119.
Chipuk JE, Bouchier-Hayes L, Kuwana T, Newmeyer DD, Green DR . (2005). PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science 309: 1732–1735.
Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M et al. (2004). Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303: 1010–1014.
Christophorou MA, Ringhausen I, Finch AJ, Brown Swigart L, Evan GI . (2006). The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 14: 214–217.
Crighton D, Wilkinson S, O'Prey J, Syed N, Harrison PR, Gasco M et al. (2006). DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 14: 121–134.
Cummins JM, Vogelstein B . (2004). HAUSP is required for p53 destabilization. Cell Cycle 3: 689–692.
Dai MS, Lu H . (2004). Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5. J Biol Chem 279: 44475–44482.
Dai MS, Zeng SX, Jin Y, Sun XX, David L, Lu H . (2004). Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Mol Biol Cell 24: 7654–7668.
Danial NN, Korsmeyer SJ . (2004). Cell death: critical control points. Cell 116: 205–219.
Dawson S, Apcher S, Mee M, Higashitsuji H, Baker R, Uhle S et al. (2002). Gankyrin is an ankyrin-repeat oncoprotein that interacts with CDK4 kinase and the S6 ATPase of the 26 S proteasome. J Biol Chem 277: 10893–10902.
de Graaf P, Little NA, Ramos YF, Meulmeester E, Letteboer SJ, Jochemsen AG . (2003). Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2. J Biol Chem 278: 38315–38324.
de Toledo SM, Azzam EI, Dahlberg WK, Gooding TB, Little JB . (2000). ATM complexes with HDM2 and promotes its rapid phosphorylation in a p53-independent manner in normal and tumor human cells exposed to ionizing radiation. Oncogene 19: 6185–6193.
DiTullio Jr RA, Mochan TA, Venere M, Bartkova J, Sehested M, Bartek J et al. (2002). 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer. Nat Cell Biol 4: 998–1002.
Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butel JS et al. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356: 215–221.
Dornan D, Shimizu H, Mah A, Dudhela T, Eby M, O'Rourke K et al. (2006). ATM engages autodegradation of the E3 ubiquitin ligase COP1 after DNA damage. Science 313: 1122–1126.
Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P et al. (2004). The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 429: 86–92.
Dumaz N, Meek DW . (1999). Serine15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2. EMBO J 18: 7002–7010.
Efeyan A, Garcia-Cao I, Herranz D, Velasco-Miguel S, Serrano M . (2006). Tumour biology: policing of oncogene activity by p53. Nature 443: 159.
El-Deiry WS, Harper JW, Oconnor PM, Velculescu VE, Canman CE, Jackman J et al. (1994). WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Research 54: 1169–1174.
Esser C, Scheffner M, Hohfeld J . (2005). The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. J Biol Chem 280: 27443–27448.
Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM . (2000). Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 275: 8945–8951.
Francoz S, Froment P, Bogaerts S, De Clercq S, Maetens M, Doumont G et al. (2006). Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proc Natl Acad Sci USA 103: 3232–3237.
Fu XY, Wang HY, Tan L, Liu SQ, Cao HF, Wu MC . (2002). Overexpression of p28/gankyrin in human hepatocellular carcinoma and its clinical significance. World J Gastroenterol 8: 638–643.
Garcia-Cao I, Garcia-Cao M, Martin-Caballero J, Criado LM, Klatt P, Flores JM et al. (2002). ‘Super p53’ mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J 21: 6225–6235.
Garcia-Cao I, Garcia-Cao M, Tomas-Loba A, Martin-Caballero J, Flores JM, Klatt P et al. (2006). Increased p53 activity does not accelerate telomere-driven ageing. EMBO Rep 7: 546–552.
Gatz SA, Wiesmuller L . (2006). p53 in recombination and repair. Cell Death Diff 13: 1003–1016.
Gilkes DM, Chen L, Chen J . (2006). MDMX regulation of p53 response to ribosomal stress. EMBO J 25: 5614–5625.
Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T et al. (2005). Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434: 907–913.
Gronroos E, Terentiev AA, Punga T, Ericsson J . (2004). YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proc Natl Acad Sci USA 101: 12165–12170.
Grossman SR . (2001). p300/CBP/p53 interaction and regulation of the p53 response. Eur J Biochem 268: 2773–2778.
Grossman SR, Deato ME, Brignone C, Chan HM, Kung AL, Tagami H et al. (2003). Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science 300: 342–344.
Grossmann J . (2002). Molecular mechanisms of ‘detachment-induced apoptosis – Anoikis’. Apoptosis 7: 247–260.
Gu J, Kawai H, Nie L, Kitao H, Wiederschain D, Jochemsen AG et al. (2002). Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. J Biol Chem 277: 19251–19254.
Gu J, Nie N, Wiederschain D, Yuan Z-M . (2001). Identification of p53 sequence elements that are required for MDM2-mediated nuclear export. Mol Cell Biol 21: 8533–8546.
Hainaut P, Hollstein M . (2000). p53 and human cancer: the first ten thousand mutations. Adv Cancer Res 77: 81–137.
Hammond EM, Giaccia AJ . (2005). The role of p53 in hypoxia-induced apoptosis. Biochem Biophys Res Commun 331: 718–725.
Higashitsuji H, Higashitsuji H, Itoh K, Sakurai T, Nagao T, Sumitomo Y et al. (2005a). The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell 8: 75–87.
Higashitsuji H, Liu Y, Mayer RJ, Fujita J . (2005b). The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation. Cell Cycle 4: 1335–1337.
Hu B, Gilkes DM, Farooqi B, Sebti SM, Chen J . (2006). MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin. J Biol Chem 281: 33030–33035.
Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M et al. (2004). Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 10: 1321–1328.
Iwakuma T, Lozano G . (2003). MDM2, an introduction. Mol Cancer Res 1: 933–1000.
Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT et al. (1994). Tumor spectrum analysis in p53-mutant mice. Current Biol 4: 1–7.
Jackson MW, Berberich SJ . (2000). MdmX protects p53 from Mdm2-mediated degradation. Mol Cell Biol 20: 1001–1007.
Jeffers JR, Parganas E, Lee Y, Yang C, Wang J, Brennan J et al. (2003). Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4: 321–328.
Jones SN, Roe AE, Donehower LA, Bradley A . (1995). Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378: 206–208.
Kahyo T, Nishida T, Yasuda H . (2001). Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol Cell 8: 713–718.
Kamijo T, van de Kamp E, Chong MJ, Zindy F, Diehl JA, Sherr CJ et al. (1999). Loss of the ARF tumor suppressor reverses premature replicative arrest but not radiation hypersensitivity arising from disabled atm function. Cancer Res 59: 2464–2469.
Kawai H, Wiederschain D, Kitao H, Stuart J, Tsai KK, Yuan ZM . (2003). DNA damage-induced MDMX degradation is mediated by MDM2. J Biol Chem 278: 45946–45953.
Khosravi R, Maya R, Gottlieb T, Oren M, Shiloh Y, Shkedy D . (1999). Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci USA 96: 14973–14977.
Krajewski M, Ozdowy P, D'Silva L, Rothweiler U, Holak TA . (2005). NMR indicates that the small molecule RITA does not block p53-MDM2 binding in vitro. Nat Med 11: 1135–1136; author reply 1136–1137.
Krieg AJ, Hammond EM, Giaccia AJ . (2006). Functional analysis of p53 binding under differential stresses. Mol Cell Biol 26: 7030–7045.
Laine A, Ronai Z . (2006). Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene [Epub ahead of print].
Laine A, Topisirovic I, Zhai D, Reed JC, Borden KL, Ronai Z . (2006). Regulation of p53 localization and activity by Ubc13. Mol Cell Biol 26: 8901–8913.
Lambert PF, Kashanchi F, Radonovich MF, Shiekhattar R, Brady JN . (1998). Phosphorylation of p53 serine 15 increases interaction with CBP. J Biol Chem 273: 33048–33053.
Le Cam L, Linares LK, Paul C, Julien E, Lacroix M, Hatchi E et al. (2006). E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation. Cell 127: 775–788.
Lee MH, Lee SW, Lee EJ, Choi SJ, Chung SS, Lee JI et al. (2006). SUMO-specific protease SUSP4 positively regulates p53 by promoting Mdm2 self-ubiquitination. Nat Cell Biol 8: 1424–1431.
Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S et al. (2003). Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 112: 779–791.
Leu JI, Dumont P, Hafey M, Murphy MP, George DL . (2004). Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nature Cell Biol 6: 443–450.
Li M, Brooks CL, Kon N, Gu W . (2004). A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell 13: 879–886.
Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W . (2003). Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302: 1972–1975.
Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J et al. (2002). Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416: 648–652.
Li T, Santockyte R, Shen RF, Tekle E, Wang G, Yang DC et al. (2006). Expression of SUMO-2/3 induced senescence through p53- and pRB-mediated pathways. J Biol Chem 281: 36221–36227.
Lindstrom MS, Jin A, Deisenroth C, Wolf GW, Zhang Y . (2006). Cancer-associated mutations in MDM2 zinc finger domain disrupt ribosomal protein interaction and attenuate MDM2-Induced p53 degradation. Mol Cell Biol [Epub ahead of print].
Logan IR, Gaughan L, McCracken SR, Sapountzi V, Leung HY, Robson CN . (2006). Human PIRH2 enhances androgen receptor signaling through inhibition of histone deacetylase 1 and is overexpressed in prostate cancer. Mol Cell Biol 26: 6502–6510.
Lohrum MA, Ludwig RL, Kubbutat MHG, Hanlon M, Vousden KH . (2003). Regulation of HDM2 activity by the ribosomal protein L11. Cancer Cell 3: 577–587.
Lohrum MAE, Woods DB, Ludwig RL, Bálint E, Vousden KH . (2001). C-terminal ubiquitination of p53 contributes to nuclear export. Mol Cell Biol 21: 8521–8532.
Longworth MS, Laimins LA . (2004). Pathogenesis of human papillomaviruses in differentiating epithelia. Microbiol Mol Biol Rev 68: 362–372.
Lu Y, Lin YZ, LaPushin R, Cuevas B, Fang X, Yu SX et al. (1999). The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene 18: 7034–7045.
Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T et al. (2004). Modulation of mammalian life span by the short isoform of p53. Genes Dev 18: 306–319.
Malkin D, Li FP, Strong LC, Fraumini Jr JF, Nelson CE, Kim DH et al. (1990). Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250: 1233–1238.
Mani A, Oh AS, Bowden ET, Lahusen T, Lorick KL, Weissman AM et al. (2006). E6AP mediates regulated proteasomal degradation of the nuclear receptor coactivator amplified in breast cancer 1 in immortalized cells. Cancer Res 66: 8680–8686.
Marine JC, Jochemsen AG . (2005). Mdmx as an essential regulator of p53 activity. Biochem Biophys Res Commun 331: 750–760.
Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME et al. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399: 271–275.
Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O et al. (2001). ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 15: 1067–1077.
McDonald III ER, El-Deiry WS . (2004). Suppression of caspase-8- and -10-associated RING proteins results in sensitization to death ligands and inhibition of tumor cell growth. Proc Natl Acad Sci USA 101: 6170–6175.
McDonough H, Patterson C . (2003). CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones 8: 303–308.
Megidish T, Xu JH, Xu CW . (2002). Activation of p53 by protein inhibitor of activated Stat1 (PIAS1). J Biol Chem 277: 8255–8259.
Melchior F, Hengst L . (2002). SUMO-1 and p53. Cell Cycle 1: 245–249.
Mendrysa SM, O'Leary KA, McElwee MK, Michalowski J, Eisenman RN, Powell DA et al. (2006). Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev 20: 16–21.
Mendrysa SM, Perry ME . (2006). Tumor suppression by p53 without accelerated aging: just enough of a good thing? Cell Cycle 5: 714–717.
Meulmeester E, Maurice MM, Boutell C, Teunisse AFAS, Ovaa H, Abraham TE et al. (2005a). Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2. Mol Cell 18: 565–576.
Meulmeester E, Pereg Y, Shiloh Y, Jochemsen AG . (2005b). ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle 4: 1166–1170.
Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P et al. (2003). p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11: 577–590.
Moll UM, LaQuaglia M, Benard J, Riou G . (1995). Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors. Proc Natl Acad Sci USA 92: 4407–4411.
Moll UM, Marchenko N, Zhang XK . (2006). p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction. Oncogene 25: 4725–4743.
Moll UM, Riou G, Levine AJ . (1992). Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. Proc Natl Acad Sci USA 89: 7262–7266.
Montes de Oca Luna R, Wagner DS, Lozano G . (1995). Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378: 203–206.
Moren A, Imamura T, Miyazono K, Heldin CH, Moustakas A . (2005). Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. J Biol Chem 280: 22115–22123.
Nagao T, Higashitsuji H, Nonoguchi K, Sakurai T, Dawson S, Mayer RJ et al. (2003). MAGE-A4 interacts with the liver oncoprotein gankyrin and suppresses its tumorigenic activity. J Biol Chem 278: 10668–10674.
Nakano K, Vousden KH . (2001). PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 7: 683–694.
Nelson V, Davis GE, Maxwell SA . (2001). A putative protein inhibitor of activated STAT (PIASy) interacts with p53 and inhibits p53-mediated transactivation but not apoptosis. Apoptosis 6: 221–234.
Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T et al. (2000). Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288: 1053–1058.
Pan Y, Chen J . (2003). MDM2 promotes ubiquitination and degradation of MDMX. Mol Cell Biol 23: 5113–5121.
Patton JT, Mayo LD, Singhi AD, Gudkov AV, Stark GR, Jackson MW . (2006). Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3. Cancer Res 66: 3169–3176.
Pietsch EC, Humbey O, Murphey ME . (2006). Polymorphisms in the p53 pathway. Oncogene 25: 1602–1611.
Pim D, Banks L . (2004). p53 polymorphic variants at codon 72 exert different effects on cell cycle progression. Int J Cancer 108: 196–199.
Poyurovsky MV, Priest C, Kentsis A, Borden KL, Pan ZQ, Pavletich N et al. (2006). EMBO J [Epub ahead of print].
Poyurovsky MV, Prives C . (2006). Unleashing the power of p53: lessons from mice and men. Genes Dev 20: 125–131.
Purdie CA, Harrison DJ, Peter A, Dobbie L, White S, Howie SE et al. (1994). Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene. Oncogene 9: 603–609.
Qi L, Heredia JE, Altarejos JY, Screaton R, Goebel N, Niessen S et al. (2006). TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science 312: 1763–1766.
Rajendra R, Malegaonkar D, Pungaliya P, Marshall H, Rasheed Z, Brownell J et al. (2004). Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J Biol Chem 279: 36440–36444.
Roe JS, Kim H, Lee SM, Kim ST, Cho EJ, Youn HD . (2006). p53 stabilization and transactivation by a von Hippel-Lindau protein. Mol Cell 22: 395–405.
Rubbi CP, Milner J . (2003). Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J 22: 6068–6077.
Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM . (2005). The antioxidant function of the p53 tumor suppressor. Nat Med 11: 1306–1313.
Sakaguchi K, Saito S, Higashimoto Y, Roy S, Anderson CW, Appella E . (2000). Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding. J Biol Chem 275: 9278–9283.
Salcedo A, Mayor Jr F, Penela P . (2006). Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2. EMBO J 25: 4752–4762.
Schmidt D, Muller S . (2002). Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci USA 99: 2872–2877.
Secombe J, Parkhurst SM . (2004). Drosophila Topors is a RING finger-containing protein that functions as a ubiquitin-protein isopeptide ligase for the hairy basic helix-loop-helix repressor protein. J Biol Chem 279: 17126–17133.
Semenza GL . (2001). HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell 107: 1–3.
Sharp DA, Kratowicz SA, Sank MJ, George DL . (1999). Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein. J Biol Chem 274: 38189–38196.
Sherr CJ . (2006). Divorcing ARF and p53: an unsettled case. Nat Rev Cancer 6: 663–673.
Sherr CJ, Roberts JM . (1999). CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13: 1501–1512.
Shieh S-Y, Ikeda M, Taya Y, Prives C . (1997). DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91: 325–334.
Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P, Bazuine M et al. (1996). MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J 15: 5349–5357.
Siliciano JD, Canman CE, Taya Y, Sakaguchi K, Appella E, Kastan MB . (1997). DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev 11: 3471–3481.
Srivastava S, Zou Z, Pirollo K, Blattner W, Chang EH . (1990). Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 348: 747–749.
Stad R, Little NA, Xirodimas DP, Frenk R, van der Eb AJ, Lane DP et al. (2001). Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep 2: 1029–1034.
Stott F, Bates SA, James M, McConnell BB, Starborg M, Brookes S et al. (1998). The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J 17: 5001–5014.
Sui G, Affar el B, Shi Y, Brignone C, Wall NR, Yin P et al. (2004). Yin Yang 1 is a negative regulator of p53. Cell 117: 859–872.
Tang J, Qu LK, Zhang J, Wang W, Michaelson JS, Degenhardt YY et al. (2006). Critical role for Daxx in regulating Mdm2. Nat Cell Biol 8: 855–862.
Tanimura S, Ohtsuka S, Mitsui K, Shirouzu K, Yoshimura A, Ohtsubo M . (1999). MDM2 interacts with MDMX through their RING finger domains. FEBS Lett 447: 5–9.
Toledo F, Wahl GM . (2006). Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 6: 909–923.
Tyner SD, Venkatachalam S, Choi J, Ghebranious N, Igelmann H, Lu X et al. (2002). p53 mutant mice that display early ageing-associated phenotypes. Nature 415: 45–53.
Uldrijan S, Pannekoek WJ, Vousden KH . (2006). EMBO J [Epub ahead of print].
Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z et al. (2004). In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303: 844–848.
Villunger A, Michalak EM, Coultas L, Mullauer F, Bock G, Ausserlechner MJ et al. (2003). p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302: 1036–1038.
Vogelstein B, Lane D, Levine AJ . (2000). Surfing the p53 network. Nature 408: 307–310.
Wade M, Wong ET, Tang M, Stommel JM, Wahl GM . (2006). Hdmx modulates the outcome of p53 activation in human tumor cells. J Biol Chem 281: 33036–33044.
Wang WJ, Kuo JC, Yao CC, Chen RH . (2002). DAP-kinase induces apoptosis by suppressing integrin activity and disrupting matrix survival signals. J Cell Biol 159: 169–179.
Watson IR, Irwin MS . (2006). Ubiquitin and ubiquitin-like modifications of the p53 family. Neoplasia 8: 655–666.
Weissman AM . (2001). Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol 2: 169–178.
Xiong S, Van Pelt CS, Elizondo-Fraire AC, Liu G, Lozano G . (2006). Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development. Proc Natl Acad Sci USA 103: 3226–3231.
Xirodimas DP, Saville MK, Bourdon JC, Hay RT, Lane DP . (2004). Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell 118: 83–97.
Yang JY, Zong CS, Xia W, Wei Y, Ali-Seyed M, Li Z et al. (2006a). MDM2 promotes cell motility and invasiveness by regulating E-cadherin degradation. Mol Cell Biol 26: 7269–7282.
Yang W, Rozan LM, McDonald III ER, Navaraj A, Liu JJ, Matthew EM et al. (2006b). Carps are ubiquitin ligases that promote MDM2-independent P53 and phospho-P53ser20 degradation. J Biol Chem [Epub ahead of print].
Yang WH, Kim JE, Nam HW, Ju JW, Kim HS, Kim YS et al. (2006c). Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat Cell Biol 8: 1074–1083.
Yang Y, Ludwig RL, Jensens JP, Pierre S, Medaglia MV, Davydov I et al. (2005). Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 7: 547–559.
Yee KS, Vousden KH . (2005). Complicating the complexity of p53. Carcinogenesis 26: 1317–1322.
Yoon KA, Nakamura Y, Arakawa H . (2004). Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J Hum Genet 49: 134–140.
Yu J, Kinzler KW, Vogelstein B, Zhang L . (2003). PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci USA 100: 1931–1936.
Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B . (2001). PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 7: 673–682.
Yuan X, Zhou Y, Casanova E, Chai M, Kiss E, Grone HJ et al. (2005). Genetic inactivation of the transcription factor TIF-IA leads to nucleolar disruption, cell cycle arrest, and p53-mediated apoptosis. Mol Cell 19: 77–87.
Zauberman A, Barak Y, Ragimov N, Levy N, Oren M . (1993). Sequence-specific DNA binding by p53: identification of target sites and lack of binding to p53 – MDM2 complexes. EMBO J 12: 2799–2808.
Zhang X, Srinivasan SV, Lingrel JB . (2004). WWP1-dependent ubiquitination and degradation of the lung Kruppel-like factor, KLF2. Biochem Biophys Res Commun 316: 139–148.
Zhang Y, Wolf GW, Bhat K, Jin A, Allio T, Burkhart WA et al. (2003). Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol 23: 8902–8912.
Zhang Z, Zhang R . (2005). p53-independent activities of MDM2 and their relevance to cancer therapy. Curr Cancer Drug Targets 5: 9–20.
Zhong Q, Gao W, Du F, Wang X . (2005). Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121: 1085–1095.
Acknowledgements
We are grateful to Cancer Research UK for support and funding.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Horn, H., Vousden, K. Coping with stress: multiple ways to activate p53. Oncogene 26, 1306–1316 (2007). https://doi.org/10.1038/sj.onc.1210263
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210263
Keywords
This article is cited by
-
Molecular mechanisms behind ROS regulation in cancer: A balancing act between augmented tumorigenesis and cell apoptosis
Archives of Toxicology (2023)
-
Of the many cellular responses activated by TP53, which ones are critical for tumour suppression?
Cell Death & Differentiation (2022)
-
Development of a novel lipid metabolism-based risk score model in hepatocellular carcinoma patients
BMC Gastroenterology (2021)
-
FBXL6 degrades phosphorylated p53 to promote tumor growth
Cell Death & Differentiation (2021)
-
Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression
Cell Death & Disease (2021)
