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Cellular functions of 14-3-3ζ in apoptosis and cell adhesion emphasize its oncogenic character

Oncogene volume 27, pages 1315–1319 (2008)Cite this article

Abstract

14-3-3 proteins are relevant to cancer biology as they are key regulators of major cellular processes such as proliferation, differentiation, senescence and apoptosis. So far, the sigma isoform (14-3-3σ) has most directly been implicated in carcinogenesis and was recognized as a tumour-suppressor gene. The other six members of the mammalian 14-3-3 gene family likely behave as oncogenes, although direct evidence supporting this view is largely circumstantial. In this report, we show that knockdown of 14-3-3ζ induces at least two isoform-specific phenotypes that are consistent with a potential oncogenic activity during tumorigenesis. Firstly, downregulation of 14-3-3ζ sensitized cells to stress-induced apoptosis and JNK/p38 signalling and secondly, it enforced cell–cell contacts and expression of adhesion proteins. Apparently, the zeta isoform restrains both cell adhesion and the cellular propensity for apoptosis, two activities that are also restrained during carcinogenesis. The assumption that 14-3-3ζ has oncogenic properties was substantiated with a web-based meta-analysis (Oncomine), revealing that 14-3-3ζ is overexpressed in various types of carcinomas. As the highly conserved human 14-3-3 gene family encodes proteins with either tumour-promoting or tumour-suppressing activities, we infer that the cellular balance between the various 14-3-3 isoforms is crucial for the proper functioning of cells.

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References

  • Arora S, Matta A, Shukla NK, Deo SV, Ralhan R . (2005). Identification of differentially expressed genes in oral squamous cell carcinoma. Mol Carcinog 42: 97–108.

    Article  CAS  Google Scholar 

  • Balda MS, Matter K . (2003). Epithelial cell adhesion and the regulation of gene expression. Trends Cell Biol 13: 310–318.

    Article  CAS  Google Scholar 

  • Beavon IR . (2000). The E-cadherin–catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer 36: 1607–1620.

    Article  CAS  Google Scholar 

  • Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE . (1988). Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol 106: 761–771.

    Article  CAS  Google Scholar 

  • Brummelkamp TR, Bernards R, Agami R . (2002). A system for stable expression of short interfering RNAs in mammalian cells. Science 296: 550–553.

    Article  CAS  Google Scholar 

  • Buckley PG, Mantripragada KK, Benetkiewicz M, Tapia-Paez I, Diaz De Stahl T, Rosenquist M et al. (2002). A full-coverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications. Hum Mol Genet 11: 3221–3229.

    Article  CAS  Google Scholar 

  • Burnworth B, Popp S, Stark HJ, Steinkraus V, Brocker EB, Hartschuh W et al. (2006). Gain of 11q/cyclin D1 overexpression is an essential early step in skin cancer development and causes abnormal tissue organization and differentiation. Oncogene 25: 4399–4412.

    Article  CAS  Google Scholar 

  • Clairotte A, Lascombe I, Fauconnet S, Mauny F, Felix S, Algros MP et al. (2006). Expression of E-cadherin and alpha-, beta-, gamma-catenins in patients with bladder cancer: identification of gamma-catenin as a new prognostic marker of neoplastic progression in T1 superficial urothelial tumors. Am J Clin Pathol 125: 119–126.

    Article  CAS  Google Scholar 

  • Dent P, Yacoub A, Fisher PB, Hagan MP, Grant S . (2003). MAPK pathways in radiation responses. Oncogene 22: 5885–5896.

    Article  CAS  Google Scholar 

  • Ghadimi BM, Grade M, Liersch T, Langer C, Siemer A, Fuzesi L et al. (2003). Gain of chromosome 8q23-24 is a predictive marker for lymph node positivity in colorectal cancer. Clin Cancer Res 9: 1808–1814.

    CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  Google Scholar 

  • Hekman M, Albert S, Galmiche A, Rennefahrt UE, Fueller J, Fischer A et al. (2006). Reversible membrane interaction of BAD requires two C-terminal lipid binding domains in conjunction with 14-3-3 protein binding. J Biol Chem 281: 17321–17336.

    Article  CAS  Google Scholar 

  • Hermeking H . (2003). The 14-3-3 cancer connection. Nat Rev Cancer 3: 931–943.

    Article  CAS  Google Scholar 

  • Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S et al. (1997). 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell 1: 3–11.

    Article  CAS  Google Scholar 

  • Jang JS, Cho HY, Lee YJ, Ha WS, Kim HW . (2004). The differential proteome profile of stomach cancer: identification of the biomarker candidates. Oncol Res 14: 491–499.

    Article  CAS  Google Scholar 

  • Jin Y, Dai MS, Lu SZ, Xu Y, Luo Z, Zhao Y et al. (2006). 14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation. EMBO J 25: 1207–1218.

    Article  CAS  Google Scholar 

  • Kim BJ, Ryu SW, Song BJ . (2006). JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J Biol Chem 281: 21256–21265.

    Article  CAS  Google Scholar 

  • Niemantsverdriet M, Jongmans W, Backendorf C . (2005). Radiation response and cell cycle regulation of p53 rescued malignant keratinocytes. Exp Cell Res 310: 237–247.

    Article  CAS  Google Scholar 

  • Porter GW, Khuri FR, Fu H . (2006). Dynamic 14-3-3/client protein interactions integrate survival and apoptotic pathways. Semin Cancer Biol 16: 193–202.

    Article  CAS  Google Scholar 

  • Rhodes DR, Chinnaiyan AM . (2005). Integrative analysis of the cancer transcriptome. Nat Genet 37 (Suppl): S31–S37.

    Article  CAS  Google Scholar 

  • Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D et al. (2004). ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6: 1–6.

    Article  CAS  Google Scholar 

  • Sugiyama A, Miyagi Y, Komiya Y, Kurabe N, Kitanaka C, Kato N et al. (2003). Forced expression of antisense 14-3-3beta RNA suppresses tumor cell growth in vitro and in vivo. Carcinogenesis 24: 1549–1559.

    Article  CAS  Google Scholar 

  • Tada K, Oka M, Tangoku A, Hayashi H, Oga A, Sasaki K . (2000). Gains of 8q23-qter and 20q and loss of 11q22-qter in esophageal squamous cell carcinoma associated with lymph node metastasis. Cancer 88: 268–273.

    Article  CAS  Google Scholar 

  • Takeuchi T, Liang SB, Ohtsuki Y . (2002). Downregulation of expression of a novel cadherin molecule, T-cadherin, in basal cell carcinoma of the skin. Mol Carcinog 35: 173–179.

    Article  CAS  Google Scholar 

  • Takihara Y, Matsuda Y, Hara J . (2000). Role of the beta isoform of 14-3-3 proteins in cellular proliferation and oncogenic transformation. Carcinogenesis 21: 2073–2077.

    Article  CAS  Google Scholar 

  • Tzivion G, Gupta VS, Kaplun L, Balan V . (2006). 14-3-3 proteins as potential oncogenes. Semin Cancer Biol 16: 203–213.

    Article  CAS  Google Scholar 

  • Ueda G, Sunakawa H, Nakamori K, Shinya T, Tsuhako W, Tamura Y et al. (2006). Aberrant expression of beta- and gamma-catenin is an independent prognostic marker in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 35: 356–361.

    Article  CAS  Google Scholar 

  • van Hemert MJ, Steensma HY, van Heusden GP . (2001). 14-3-3 proteins: key regulators of cell division, signalling and apoptosis. BioEssays 23: 936–946.

    Article  CAS  Google Scholar 

  • Wang B, Liu K, Lin FT, Lin WC . (2004). A role for 14-3-3 tau in E2F1 stabilization and DNA damage-induced apoptosis. J Biol Chem 279: 54140–54152.

    Article  CAS  Google Scholar 

  • Wanzel M, Kleine-Kohlbrecher D, Herold S, Hock A, Berns K, Park J et al. (2005). Akt and 14-3-3eta regulate Miz1 to control cell-cycle arrest after DNA damage. Nat Cell Biol 7: 30–41.

    Article  CAS  Google Scholar 

  • Zang L, Palmer Toy D, Hancock WS, Sgroi DC, Karger BL . (2004). Proteomic analysis of ductal carcinoma of the breast using laser capture microdissection, LC-MS, and 16O/18O isotopic labeling. J Proteome Res 3: 604–612.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank Dr H van Dam (Leiden) for the p-JNK and the p-p38 antibodies, Kim Janssen and Mohammed Hamdi for technical assistance, Dr N Fusenig (Heidelberg) for HaCaT cells and Dr R Agami (Amsterdam) for the pSuper plasmid. Drs A Visser, M Noteborn and J Brouwer (Leiden) are acknowledged for critically reading this paper.

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  1. M Niemantsverdriet

    Present address: 2Current address: Radiation and Stress Cell Biology, Department of Cell Biology, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.,

Authors and Affiliations

  1. Laboratory of Molecular Genetics, Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands

    M Niemantsverdriet, K Wagner, M Visser & C Backendorf

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  1. M Niemantsverdriet
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  2. K Wagner
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Correspondence to C Backendorf.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Niemantsverdriet, M., Wagner, K., Visser, M. et al. Cellular functions of 14-3-3ζ in apoptosis and cell adhesion emphasize its oncogenic character. Oncogene 27, 1315–1319 (2008). https://doi.org/10.1038/sj.onc.1210742

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