Abstract
β-catenin is involved in both cell–cell interactions and wnt pathway–dependent cell fate determination through its interactions with E-cadherin and TCF/LEF transcription factors, respectively. Cytoplasmic/nuclear levels of β-catenin are important in regulated transcriptional activation of TCF/LEF target genes. Normally, these levels are kept low by proteosomal degradation of β-catenin through Axin1- and APC-dependent phosphorylation by CKI and GSK-3β. Deregulation of β-catenin degradation results in its aberrant accumulation, often leading to cancer. Accordingly, aberrant accumulation of β-catenin is observed at high frequency in many cancers. This accumulation correlates with either mutational activation of CTNNB1 (β-catenin) or mutational inactivation of APC and Axin1 genes in some tumors. However, there are many tumors that display β-catenin accumulation in the absence of a mutation in these genes. Thus, there must be additional sources for aberrant β-catenin accumulation in cancer cells. Here, we provide experimental evidence that wild-type β-catenin accumulates in hepatocellular carcinoma (HCC) cells in association with mutational inactivation of p53 gene. We also show that worldwide p53 and β-catenin mutation rates are inversely correlated in HCC. These data suggest that inactivation of p53 is an important cause of aberrant accumulation of β-catenin in cancer cells.
Similar content being viewed by others
References
Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I . 2002 Genes Dev. 16: 1066–1076
Barker N, Morin PJ, Clevers H . 2000 Adv. Cancer Res. 77: 1–24
Bressac B, Kew M, Wands J, Ozturk M . 1991 Nature 350: 429–431
Buendia MA . 2000 Seminars in Cancer Biology 10: 185–200
Cadoret A, Ovejero C, Saadi-Kheddouci S, Souil E, Fabre M, Romagnolo B, Kahn A, Perret C . 2001 Cancer Res. 61: 3245–3249
Calvisi DF, Factor VM, Loi R, Thorgeirsson SS . 2001 Cancer Res. 61: 2085–2091
Candidus S, Bischoff P, Becker KF, Hofler H . 1996 Cancer Res. 56: 49–52
Chung DC . 2000 Gastroenterology 119: 854–865
Damalas A, Ben-Ze'ev A, Simcha I, Shtutman M, Leal JF, Zhurinsky J, Geiger B, Oren M . 1999 EMBO J. 18: 3054–3063
Damalas A, Kahan S, Shtutman M, Ben-Ze'ev A, Oren M . 2001 EMBO J. 20: 4912–4922
de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C . 1998 Proc. Natl. Acad. Sci. USA 95: 8847–8851
Devereux TR, Stern MC, Flake GP, Yu MC, Zhang ZQ, London SJ, Taylor JA . 2001 Mol. Carcinog. 31: 68–73
Frebourg T, Barbier N, Kassel J, Ng YS, Romero P, Friend SH . 1992 Cancer Res. 52: 6976–6978
Friedlander P, Haupt Y, Prives C, Oren M . 1996 Mol. Cell. Biol. 16: 4961–4971
Fujie H, Moriya K, Shintani Y, Tsutsumi T, Takayama T, Makuuchi M, Kimura S, Koike K . 2001 Hepatol. Res. 20: 39–51
Handerson BR . 2000 Nature Cell Biology 2: 653–660
He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW . 1998 Science, 281: 1509–1512
Hommura F, Furuuchi K, Yamazaki K, Ogura S, Kinoshita I, Shimizu M, Moriuchi T, Katoh H, Nishimura M, Dosaka-Akita H . 2002 Cancer 94: 752–758
Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC . 1991 Nature 350: 427–428
Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY . 2000 Am. J. Pathol. 157: 763–770
Huang H, Fuji H, Sankila A, Mahler-Araujo BM, Matsuda M, Cathomas G, Ohgaki H . 1999 Am. J. Pathol. 155: 1795–1801
Inagawa S, Itabashi M, Adachi S, Kawamoto T, Hori M, Shimazaki J, Yoshimi F, Fukao K . 2002 Clin. Cancer Res. 8: 450–456
Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, Kittel A, Saitoh T . 1995 Neuron 14: 467–475
Johnsson M, Borg A, Nilbert M, Andersson T . 2000 Eur. J. Cancer 36: 242–248
Kinzler KW, Volgelstein B . 1998 The Genetics Basis of Human Cancer: Colorectal Tumors Kinzler KW and Volgelstein B (eds) New York: McGraw-Hill pp 565–587
Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T . 1999 Cancer Res. 59: 269–273
Kondo Y, Kanai Y, Sakamoto M, Genda T, Mizokami M, Ueda R, Hirohashi S . 1999 Jpn. J. Cancer Res. 90: 1301–1309
Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, Monges G, Thomas G, Bioulac-Sage P, Zucman-Rossi J . 2001 Gastroenterology 120: 1763–1773
Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, Pestell RG, Hung MC . 2000 Proc. Natl. Acad. Sci. USA 97: 4262–4266
Liu J, Stevens J, Rote CA, Yost HJ, Hu Y, Neufeld KL, White RL, Matsunami N . 2001 Molecular Cell 7: 927–936
Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X . 2002 Cell 108: 837–847
Matsuzawa S, Reed JC . 2001 Molecular Cell 7: 915–926
Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T, Nakamura Y . 1998 Cancer Res. 58: 2524–2527
Monga SP, Pediaditakis P, Mule K, Stolz DB, Michalopoulos GK . 2001 Hepatology 33: 1098–1109
Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES, Buendia MA . 1999 Am. J. Pathol. 155: 703–710
Olivier M, Eeles R, Hollstein M, Khan MA, Harris CC, Hainaut P . 2002 Human Mutation 19: 607–617
Ozdag H, Tez M, Sayek I, Muslumanoglu M, Tarcan O, Icli F, Ozturk M, Ozcelik T . 2000 Eur. J. Cancer 36: 2076–2082
Ozturk M . 1991 Lancet 338: 1356–1359
Ozturk M . 1999 Semin. Liver Dis. 19: 235–242
Park WS, Oh RR, Park JY, Kim PJ, Shin MS, Lee JH, Kim HS, Lee SH, Kim SY, Park YG, An WG, Kim HS, Jang JJ, Yoo NJ, Lee JY . 2001 J. Pathol. 193: 483–490
Pipas JM, Levine AJ . 2001 Semin. Cancer Biol. 11: 23–30
Polakis P . 2000 Genes Dev. 14: 1837–1851
Ponchel F, Puisieux A, Tabone E, Michot JP, Froschl G, Morel AP, Frebourg T, Fontaniere B, Oberhammer F, Ozturk M . 1994 Cancer Res. 54: 2064–2068
Renard CA, Fourel G, Bralet MP, Degott C, De La Coste A, Perret C, Tiollais P, Buendia MA . 2000 Oncogene 19: 2678–2686
Rimm DL, Caca K, Hu G, Harrison FB, Fearon ER . 1999 Am. J. Pathol. 154: 325–329
Ryan KM, Phillips AC, Vousden KH . 2001 Curr. Opin. Cell Biol. 13: 332–337
Sadot E, Geiger B, Oren M, Ben Ze'ev A . 2001 Mol. Cell Biol. 21: 6768–6781
Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y . 2000 Nat. Genet. 24: 245–250
Sayan AE, Sayan BS, Findikli N, Ozturk M . 2001a Oncogene 20: 5111–5117
Sayan BS, Ince G, Sayan AE, Ozturk M . 2001b J. Cell Biol. 155: 719–724
Shinohara A, Yokoyama Y, Wan X, Takahashi Y, Mori Y, Takami T, Shimokawa K, Tamaya T . 2001 Gynecol. Oncol. 82: 450–455
Sparks AB, Morin PJ, Vogelstein B, Kinzler KW . 1998 Cancer Res. 58: 1130–1134
Terris B, Pineau P, Bregeaud L, Valla D, Belghiti J, Tiollais P, Degott C, Dejean A . 1999 Oncogene 18: 6583–6588
Tetsu O, McCormick F . 1999 Nature 398: 422–426
Ueda M, Gemmill RM, West J, Winn R, Sugita M, Tanaka N, Ueki M, Drabkin HA . 2001 Br. J. Cancer 85: 64–68
Umeda T, Yamamoto T, Kajino K, Hino O . 2000 Int. J. Oncol. 16: 1133–1136
Unsal H, Yakicier C, Marcais C, Kew M, Volkmann M, Zentgraf H, Isselbacher KJ, Ozturk M . 1994 Proc. Natl. Acad. Sci. USA 91: 822–826
Wei Y, Fabre M, Branchereau S, Gauthier F, Perilongo G, Buendia MA . 2000 Oncogene 19: 498–504
Wong CM, Fan ST, Ng IO . 2001 Cancer, 92: 136–145
Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M . 1999 Oncogene 18: 4879–4883
Yolcu E, Sayan BS, Yagci T, Cetin-Atalay R, Soussi T, Yurdusev N, Ozturk M . 2001 Oncogene 20: 1398–13401
Acknowledgements
This work was supported by grants from Tubitak and Bilkent University. We thank S Friend (USA) and T Frebourg (France) for p53 expression plasmids and T Arayici for technical help in DNA sequencing.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cagatay, T., Ozturk, M. p53 mutation as a source of aberrant β-catenin accumulation in cancer cells. Oncogene 21, 7971–7980 (2002). https://doi.org/10.1038/sj.onc.1205919
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205919
- Springer Nature Limited
Keywords
This article is cited by
-
ZMIZ2 facilitates hepatocellular carcinoma progression via LEF1 mediated activation of Wnt/β-catenin pathway
Experimental Hematology & Oncology (2024)
-
Mutant p53 gain-of-function stimulates canonical Wnt signaling via PI3K/AKT pathway in colon cancer
Journal of Cell Communication and Signaling (2023)
-
Pan-cancer pervasive upregulation of 3′ UTR splicing drives tumourigenesis
Nature Cell Biology (2022)
-
Characterisation of resistance mechanisms developed by basal cell carcinoma cells in response to repeated cycles of Photodynamic Therapy
Scientific Reports (2019)
-
Liver cancer with concomitant TP53 and CTNNB1 mutations: a case report
BMC Clinical Pathology (2016)