• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Jun 1, 1999; 18(11): 3054–3063.
PMCID: PMC1171387

Excess beta-catenin promotes accumulation of transcriptionally active p53.

Abstract

beta-catenin is a multifunctional protein, acting both as a structural component of the cell adhesion machinery and as a transducer of extracellular signals. Deregulated beta-catenin protein expression, due to mutations in the beta-catenin gene itself or in its upstream regulator, the adenomatous polyposis coli (APC) gene, is prevalent in colorectal cancer and in several other tumor types, and attests to the potential oncogenic activity of this protein. Increased expression of beta-catenin is an early event in colorectal carcinogenesis, and is usually followed by a later mutational inactivation of the p53 tumor suppressor. To examine whether these two key steps in carcinogenesis are interrelated, we studied the effect of excess beta-catenin on p53. We report here that overexpression of beta-catenin results in accumulation of p53, apparently through interference with its proteolytic degradation. This effect involves both Mdm2-dependent and -independent p53 degradation pathways, and is accompanied by augmented transcriptional activity of p53 in the affected cells. Increased p53 activity may provide a safeguard against oncogenic deregulation of beta-catenin, and thus impose a pressure for mutational inactivation of p53 during the later stages of tumor progression.

Full Text

The Full Text of this article is available as a PDF (300K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997 Jul 1;16(13):3797–3804. [PMC free article] [PubMed]
  • Agarwal ML, Taylor WR, Chernov MV, Chernova OB, Stark GR. The p53 network. J Biol Chem. 1998 Jan 2;273(1):1–4. [PubMed]
  • Ahmed Y, Hayashi S, Levine A, Wieschaus E. Regulation of armadillo by a Drosophila APC inhibits neuronal apoptosis during retinal development. Cell. 1998 Jun 26;93(7):1171–1182. [PubMed]
  • Almog N, Rotter V. An insight into the life of p53: a protein coping with many functions! Review of the 9th p53 Workshop, Crete, May 9-13, 1998. Biochim Biophys Acta. 1998 Nov 26;1378(3):R43–R54. [PubMed]
  • Bedi A, Pasricha PJ, Akhtar AJ, Barber JP, Bedi GC, Giardiello FM, Zehnbauer BA, Hamilton SR, Jones RJ. Inhibition of apoptosis during development of colorectal cancer. Cancer Res. 1995 May 1;55(9):1811–1816. [PubMed]
  • Behrens J, von Kries JP, Kühl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature. 1996 Aug 15;382(6592):638–642. [PubMed]
  • Behrens J, Jerchow BA, Würtele M, Grimm J, Asbrand C, Wirtz R, Kühl M, Wedlich D, Birchmeier W. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science. 1998 Apr 24;280(5363):596–599. [PubMed]
  • Ben-Ze'ev A, Geiger B. Differential molecular interactions of beta-catenin and plakoglobin in adhesion, signaling and cancer. Curr Opin Cell Biol. 1998 Oct;10(5):629–639. [PubMed]
  • Bennett WP. p53 alterations in progenitor lesions of the bronchus, esophagus, oral cavity, and colon. Cancer Detect Prev. 1995;19(6):503–511. [PubMed]
  • Böttger A, Böttger V, Sparks A, Liu WL, Howard SF, Lane DP. Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo. Curr Biol. 1997 Nov 1;7(11):860–869. [PubMed]
  • Bukholm IK, Nesland JM, Kåresen R, Jacobsen U, Børresen-Dale AL. Expression of E-cadherin and its relation to the p53 protein status in human breast carcinomas. Virchows Arch. 1997 Nov;431(5):317–321. [PubMed]
  • Bullions LC, Levine AJ. The role of beta-catenin in cell adhesion, signal transduction, and cancer. Curr Opin Oncol. 1998 Jan;10(1):81–87. [PubMed]
  • Charpin C, Garcia S, Bouvier C, Devictor B, Andrac L, Choux R, Lavaut M. E-cadherin quantitative immunocytochemical assays in breast carcinomas. J Pathol. 1997 Mar;181(3):294–300. [PubMed]
  • Chen J, Marechal V, Levine AJ. Mapping of the p53 and mdm-2 interaction domains. Mol Cell Biol. 1993 Jul;13(7):4107–4114. [PMC free article] [PubMed]
  • Clevers H, van de Wetering M. TCF/LEF factor earn their wings. Trends Genet. 1997 Dec;13(12):485–489. [PubMed]
  • de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8847–8851. [PMC free article] [PubMed]
  • Cox RT, Peifer M. Wingless signaling: the inconvenient complexities of life. Curr Biol. 1998 Feb 12;8(4):R140–R144. [PubMed]
  • de Stanchina E, McCurrach ME, Zindy F, Shieh SY, Ferbeyre G, Samuelson AV, Prives C, Roussel MF, Sherr CJ, Lowe SW. E1A signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev. 1998 Aug 1;12(15):2434–2442. [PMC free article] [PubMed]
  • Donehower LA, Godley LA, Aldaz CM, Pyle R, Shi YP, Pinkel D, Gray J, Bradley A, Medina D, Varmus HE. Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability. Genes Dev. 1995 Apr 1;9(7):882–895. [PubMed]
  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. [PubMed]
  • Fazeli A, Steen RG, Dickinson SL, Bautista D, Dietrich WF, Bronson RT, Bresalier RS, Lander ES, Costa J, Weinberg RA. Effects of p53 mutations on apoptosis in mouse intestinal and human colonic adenomas. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10199–10204. [PMC free article] [PubMed]
  • Friedlander P, Haupt Y, Prives C, Oren M. A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis. Mol Cell Biol. 1996 Sep;16(9):4961–4971. [PMC free article] [PubMed]
  • Giaccia AJ, Kastan MB. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev. 1998 Oct 1;12(19):2973–2983. [PubMed]
  • Gumbiner BM. Carcinogenesis: a balance between beta-catenin and APC. Curr Biol. 1997 Jul 1;7(7):R443–R446. [PubMed]
  • Hansen R, Oren M. p53; from inductive signal to cellular effect. Curr Opin Genet Dev. 1997 Feb;7(1):46–51. [PubMed]
  • Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P. Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol. 1998 May 7;8(10):573–581. [PubMed]
  • Hart M, Concordet JP, Lassot I, Albert I, del los Santos R, Durand H, Perret C, Rubinfeld B, Margottin F, Benarous R, et al. The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr Biol. 1999 Feb 25;9(4):207–210. [PubMed]
  • Harvey DM, Levine AJ. p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts. Genes Dev. 1991 Dec;5(12B):2375–2385. [PubMed]
  • Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997 May 15;387(6630):296–299. [PubMed]
  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW. Identification of c-MYC as a target of the APC pathway. Science. 1998 Sep 4;281(5382):1509–1512. [PubMed]
  • Hermeking H, Eick D. Mediation of c-Myc-induced apoptosis by p53. Science. 1994 Sep 30;265(5181):2091–2093. [PubMed]
  • Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997 Dec 22;420(1):25–27. [PubMed]
  • Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 1998 Mar 2;17(5):1371–1384. [PMC free article] [PubMed]
  • Ilyas M, Tomlinson IP, Rowan A, Pignatelli M, Bodmer WF. Beta-catenin mutations in cell lines established from human colorectal cancers. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10330–10334. [PMC free article] [PubMed]
  • Inomata M, Ochiai A, Akimoto S, Kitano S, Hirohashi S. Alteration of beta-catenin expression in colonic epithelial cells of familial adenomatous polyposis patients. Cancer Res. 1996 May 1;56(9):2213–2217. [PubMed]
  • Israeli D, Tessler E, Haupt Y, Elkeles A, Wilder S, Amson R, Telerman A, Oren M. A novel p53-inducible gene, PAG608, encodes a nuclear zinc finger protein whose overexpression promotes apoptosis. EMBO J. 1997 Jul 16;16(14):4384–4392. [PMC free article] [PubMed]
  • Johnston LA, Edgar BA. Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing. Nature. 1998 Jul 2;394(6688):82–84. [PubMed]
  • Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8292–8297. [PMC free article] [PubMed]
  • Kantak SS, Kramer RH. E-cadherin regulates anchorage-independent growth and survival in oral squamous cell carcinoma cells. J Biol Chem. 1998 Jul 3;273(27):16953–16961. [PubMed]
  • Kashiwagi H, Spigelman AD, Talbot IC, Debinski HS, McKie AB, Lemoine NR, Phillips RK. p53 and K-ras status in duodenal adenomas in familial adenomatous polyposis. Br J Surg. 1997 Jun;84(6):826–829. [PubMed]
  • Kemler R. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet. 1993 Sep;9(9):317–321. [PubMed]
  • Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996 Oct 18;87(2):159–170. [PubMed]
  • Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science. 1997 Mar 21;275(5307):1784–1787. [PubMed]
  • Kubbutat MH, Vousden KH. Keeping an old friend under control: regulation of p53 stability. Mol Med Today. 1998 Jun;4(6):250–256. [PubMed]
  • Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature. 1997 May 15;387(6630):299–303. [PubMed]
  • Latres E, Chiaur DS, Pagano M. The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin. Oncogene. 1999 Jan 28;18(4):849–854. [PubMed]
  • Levi E, Stryker SJ, Rao MS. p53 Protein overexpression in colorectal tumors from patients with familial adenomatous polyposis: is it an early or late event? Am J Gastroenterol. 1996 Jan;91(1):11–14. [PubMed]
  • Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997 Feb 7;88(3):323–331. [PubMed]
  • Lozano G, Montes de Oca Luna R. MDM2 function. Biochim Biophys Acta. 1998 Apr 17;1377(2):M55–M59. [PubMed]
  • McMasters KM, Montes de Oca Luna R, Peña JR, Lozano G. mdm2 deletion does not alter growth characteristics of p53-deficient embryo fibroblasts. Oncogene. 1996 Oct 17;13(8):1731–1736. [PubMed]
  • Mahmoud NN, Boolbol SK, Bilinski RT, Martucci C, Chadburn A, Bertagnolli MM. Apc gene mutation is associated with a dominant-negative effect upon intestinal cell migration. Cancer Res. 1997 Nov 15;57(22):5045–5050. [PubMed]
  • Maki CG, Huibregtse JM, Howley PM. In vivo ubiquitination and proteasome-mediated degradation of p53(1). Cancer Res. 1996 Jun 1;56(11):2649–2654. [PubMed]
  • Mitsudomi T, Steinberg SM, Nau MM, Carbone D, D'Amico D, Bodner S, Oie HK, Linnoila RI, Mulshine JL, Minna JD, et al. p53 gene mutations in non-small-cell lung cancer cell lines and their correlation with the presence of ras mutations and clinical features. Oncogene. 1992 Jan;7(1):171–180. [PubMed]
  • Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T, Nakamura Y. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res. 1998 Jun 15;58(12):2524–2527. [PubMed]
  • Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destrée O, Clevers H. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell. 1996 Aug 9;86(3):391–399. [PubMed]
  • Morin PJ, Vogelstein B, Kinzler KW. Apoptosis and APC in colorectal tumorigenesis. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7950–7954. [PMC free article] [PubMed]
  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997 Mar 21;275(5307):1787–1790. [PubMed]
  • Muller AJ, Young JC, Pendergast AM, Pondel M, Landau NR, Littman DR, Witte ON. BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias. Mol Cell Biol. 1991 Apr;11(4):1785–1792. [PMC free article] [PubMed]
  • Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P. Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3046–3050. [PMC free article] [PubMed]
  • Nigro JM, Aldape KD, Hess SM, Tlsty TD. Cellular adhesion regulates p53 protein levels in primary human keratinocytes. Cancer Res. 1997 Sep 1;57(17):3635–3639. [PubMed]
  • Okamoto K, Beach D. Cyclin G is a transcriptional target of the p53 tumor suppressor protein. EMBO J. 1994 Oct 17;13(20):4816–4822. [PMC free article] [PubMed]
  • Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9;78(5):773–785. [PubMed]
  • Peifer M. Beta-catenin as oncogene: the smoking gun. Science. 1997 Mar 21;275(5307):1752–1753. [PubMed]
  • Polakis P. The adenomatous polyposis coli (APC) tumor suppressor. Biochim Biophys Acta. 1997 Jun 7;1332(3):F127–F147. [PubMed]
  • Pomerantz J, Schreiber-Agus N, Liégeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell. 1998 Mar 20;92(6):713–723. [PubMed]
  • Prives C. Signaling to p53: breaking the MDM2-p53 circuit. Cell. 1998 Oct 2;95(1):5–8. [PubMed]
  • Riese J, Yu X, Munnerlyn A, Eresh S, Hsu SC, Grosschedl R, Bienz M. LEF-1, a nuclear factor coordinating signaling inputs from wingless and decapentaplegic. Cell. 1997 Mar 21;88(6):777–787. [PubMed]
  • Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science. 1997 Mar 21;275(5307):1790–1792. [PubMed]
  • Salomon D, Sacco PA, Roy SG, Simcha I, Johnson KR, Wheelock MJ, Ben-Ze'ev A. Regulation of beta-catenin levels and localization by overexpression of plakoglobin and inhibition of the ubiquitin-proteasome system. J Cell Biol. 1997 Dec 1;139(5):1325–1335. [PMC free article] [PubMed]
  • Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997 Mar 7;88(5):593–602. [PubMed]
  • Shaulian E, Zauberman A, Ginsberg D, Oren M. Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding. Mol Cell Biol. 1992 Dec;12(12):5581–5592. [PMC free article] [PubMed]
  • Simcha I, Shtutman M, Salomon D, Zhurinsky J, Sadot E, Geiger B, Ben-Ze'ev A. Differential nuclear translocation and transactivation potential of beta-catenin and plakoglobin. J Cell Biol. 1998 Jun 15;141(6):1433–1448. [PMC free article] [PubMed]
  • Sokol SY. Analysis of Dishevelled signalling pathways during Xenopus development. Curr Biol. 1996 Nov 1;6(11):1456–1467. [PubMed]
  • Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res. 1998 Mar 15;58(6):1130–1134. [PubMed]
  • Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999 Apr 1;398(6726):422–426. [PubMed]
  • Tominaga O, Hamelin R, Trouvat V, Salmon RJ, Lesec G, Thomas G, Remvikos Y. Frequently elevated content of immunochemically defined wild-type p53 protein in colorectal adenomas. Oncogene. 1993 Oct;8(10):2653–2658. [PubMed]
  • van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, et al. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell. 1997 Mar 21;88(6):789–799. [PubMed]
  • Wagner AJ, Kokontis JM, Hay N. Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. Genes Dev. 1994 Dec 1;8(23):2817–2830. [PubMed]
  • Willert K, Nusse R. Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev. 1998 Feb;8(1):95–102. [PubMed]
  • Williams AC, Browne SJ, Yeudal WA, Paterson IC, Marshall CJ, Lane DP, Paraskeva C. Molecular events including p53 and k-ras alterations in the in vitro progression of a human colorectal adenoma cell line to an adenocarcinoma. Oncogene. 1993 Nov;8(11):3063–3072. [PubMed]
  • Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW. The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev. 1999 Feb 1;13(3):270–283. [PMC free article] [PubMed]
  • Zauberman A, Lupo A, Oren M. Identification of p53 target genes through immune selection of genomic DNA: the cyclin G gene contains two distinct p53 binding sites. Oncogene. 1995 Jun 15;10(12):2361–2366. [PubMed]
  • Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 1998 Mar 20;92(6):725–734. [PubMed]
  • Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 1998 Aug 1;12(15):2424–2433. [PMC free article] [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...