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The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis

Oncogene volume 28, pages 3915–3925 (2009)Cite this article

Abstract

The functional diversity of the tumor suppressor protein p53 is mainly regulated by protein interactions. In this study, we describe a new interaction with the peptidyl-prolyl cis/trans isomerase cyclophilin 18 (Cyp18). The interaction reduced the sequence-specific DNA binding of p53 in vitro, whereas the inhibition of the interaction increased p53-reporter gene activity in vivo. The active site of the folding helper enzyme Cyp18 was directly involved in binding. The proline-rich region (amino acids 64–91) of p53 was most likely responsible for the observed binding because a synthetic peptide comprising amino acids 68–81 of p53 inhibited this interaction, and a p53 variant containing a proline residue at position 72 (p53P72) interacted with Cyp18 more effectively than the corresponding p53R72 variant. Impairment of the Cyp18–p53 interaction induced an accumulation of cells in the G2/M phase of the cell cycle, which was more pronounced when p53P72 was expressed compared with p53R72 in an otherwise isogenic cellular background. Moreover, p53-dependent apoptosis was elevated in Cyp18 knockout cells, suggesting an antiapoptotic potential of Cyp18–p53 complexes. Functional in vivo data hint to a possible clinical relevance of the p53–Cyp18 interaction observed.

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References

  • Akakura S, Yoshida M, Yoneda Y, Horinouchi S . (2001). A role for Hsc70 in regulating nucleocytoplasmic transport of a temperature-sensitive p53 (p53Val-135). J Biol Chem 276: 14649–14657.

    Article  CAS  Google Scholar 

  • Albrechtsen N, Dornreiter I, Grosse F, Kim E, Wiesmüller L, Deppert W . (1999). Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53. Oncogene 18: 7706–7717.

    Article  CAS  Google Scholar 

  • Arévalo-Rodríguez M, Cardenas ME, Wu X, Hanes SD, Heitman J . (2000). Cyclophilin A and Ess1 interact with and regulate silencing by the Sin3-Rpd3 histone deacetylase. EMBO J 19: 3739–3749.

    Article  Google Scholar 

  • Bauerschmidt C, Pollok S, Kremmer E, Nasheuer HP, Grosse F . (2007). Interactions of human Cdc45 with the Mcm2-7 complex, the GINS complex, and DNA polymerases delta and epsilon during S phase. Genes Cells 12: 745–758.

    CAS  PubMed  Google Scholar 

  • Bergamaschi D, Samuels Y, Sullivan A, Zvelebil M, Breyssens H, Bisso A et al. (2006). iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. Nat Genet 38: 1133–1141.

    Article  CAS  Google Scholar 

  • Braaten D, Luban J . (2001). Cyclophilin A regulates HIV-1 infectivity, as demonstrated by gene targeting in human T cells. EMBO J 20: 1300–1309.

    Article  CAS  Google Scholar 

  • Choi KJ, Piao YJ, Lim MJ, Kim JH, Ha J, Choe W et al. (2007). Overexpressed cyclophilin A in cancer cells renders resistance to hypoxia- and cisplatin-induced cell death. Cancer Res 67: 3654–3662.

    Article  CAS  Google Scholar 

  • Dumont P, Leu JI, Della Pietra ACr, George DL, Murphy M . (2003). The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33: 357–365.

    Article  CAS  Google Scholar 

  • Fanghänel J . (2003). Enzymatic catalysis of the peptidyl-prolyl bond rotation: are transition state formation and enzyme dynamics directly linked? Angew Chem Int Ed Engl 42: 490–492.

    Article  Google Scholar 

  • Fischer G, Bang H, Mech C . (1984). Determination of enzymatic catalysis for the cis-trans-isomerization of peptide binding in proline-containing peptides. Biomed Biochim Acta 43: 1101–1111.

    CAS  PubMed  Google Scholar 

  • Fischer G, Wittmann-Liebold B, Lang K, Kiefhaber T, Schmid FX . (1989). Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 337: 476–478.

    Article  CAS  Google Scholar 

  • Fujimori F, Takahashi K, Uchida C, Uchida T . (1999). Mice lacking Pin1 develop normally, but are defective in entering cell cycle from G(0) arrest. Biochem Biophys Res Comm 265: 658–663.

    Article  CAS  Google Scholar 

  • Gamble TR, Vajdos FF, Yoo S, Worthylake DK, Houseweart M, Sundquist WI et al. (1996). Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid. Cell 87: 1285–1294.

    Article  CAS  Google Scholar 

  • Harding MW, Handschumacher RE, Speicher DW . (1986). Isolation and amino acid sequence of cyclophilin. J Biol Chem 261: 8547–8555.

    CAS  PubMed  Google Scholar 

  • Harrison RK, Stein RL . (1990). Mechanistic studies of peptidyl prolyl cis-trans isomerase: evidence for catalysis by distortion. Biochemistry 29: 1684–1689.

    Article  CAS  Google Scholar 

  • Herman M, Weinstein T, Korzets A, Chagnac A, Ori Y, Zevin D et al. (2001). Effect of cyclosporin A on DNA repair and cancer incidence in kidney transplant recipients. J Lab Clin Med 137: 14–20.

    Article  CAS  Google Scholar 

  • Howard BA, Furumai R, Campa MJ, Rabbani ZN, Vujaskovic Z, Wang XF et al. (2005). Stable RNA interference-mediated suppression of cyclophilin A diminishes non-small-cell lung tumor growth in vivo. Cancer Res 65: 8853–8860.

    Article  CAS  Google Scholar 

  • Howard BA, Zheng Z, Campa MJ, Wang MZ, Sharma A, Haura E et al. (2004). Translating biomarkers into clinical practice: prognostic implications of cyclophilin A and macrophage migratory inhibitory factor identified from protein expression profiles in non-small cell lung cancer. Lung Cancer 46: 313–323.

    Article  Google Scholar 

  • Hsu T, McRackan D, Vincent TS, Gert de Couet H . (2001). Drosophila Pin1 prolyl isomerase Dodo is a MAP kinase signal responder during oogenesis. Nature Cell Biol 3: 538–543.

    Article  CAS  Google Scholar 

  • Jensen P, Hansen S, Møller B, Leivestad T, Pfeffer P, Geiran O et al. (1999). Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 40: 177–186.

    Article  CAS  Google Scholar 

  • Johnson MD, Kinoshita Y, Xiang H, Ghatan S, Morrison RS . (1999). Contribution of p53-dependent caspase activation to neuronal cell death declines with neuronal maturation. J Neurosci 19: 2996–3006.

    Article  CAS  Google Scholar 

  • King FW, Wawrzynow A, Hohfeld J, Zylicz M . (2001). Co-chaperones Bag-1, Hop and Hsp40 regulate Hsc70 and Hsp90 interactions with wild-type or mutant p53. EMBO J 20: 6297–6305.

    Article  CAS  Google Scholar 

  • Lamb P, Crawford L . (1986). Characterization of the human p53 gene. Mol Cell Biol 6: 1379–1385.

    Article  CAS  Google Scholar 

  • Laptenko O, Prives C . (2006). Transcriptional regulation by p53: one protein, many possibilities. Cell Death Differ 13: 951–961.

    Article  CAS  Google Scholar 

  • Larsson R, Bergh J, Nygren P . (1991). Combination of cyclosporin A and buthionine sulfoximine (BSO) as a pharmacological strategy for circumvention of multidrug resistance in small cell lung cancer cell lines selected for resistance to doxorubicin. Anticancer Res 11: 455–459.

    CAS  PubMed  Google Scholar 

  • Liou YC, Ryo A, Huang HK, Lu PJ, Bronson R, Fujimori F et al. (2002). Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proc Natl Acad Sci USA 99: 1335–1340.

    Article  CAS  Google Scholar 

  • Liu W, Youn HD, Zhou XZ, Lu KP, Liu JO . (2001). Binding and regulation of the transcription factor NFAT by the peptidyl prolyl cis-trans isomerase Pin1. FEBS Lett 496: 105–108.

    Article  CAS  Google Scholar 

  • Ma L, Wagner J, Rice JJ, Hu W, Levine AJ, Stolovitzky GA . (2005). A plausible model for the digital response of p53 to DNA damage. Proc Natl Acad Sci USA 102: 14266–14271.

    Article  CAS  Google Scholar 

  • Marks WH, Harding MW, Handschumacher R, Marks C, Lorber MI . (1991). The immunochemical distribution of cyclophilin in normal mammalian tissues. Transplantation 52: 340–345.

    Article  CAS  Google Scholar 

  • Matlashewski GJ, Tuck S, Pim D, Lamb P, Schneider J, Crawford LV . (1987). Primary structure polymorphism at amino acid residue 72 of human p53. Mol Cell Biol 7: 961–963.

    Article  CAS  Google Scholar 

  • Pinton P, Rimessi A, Marchi S, Orsini F, Migliaccio E, Giorgio M et al. (2007). Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science 315: 659–663.

    Article  CAS  Google Scholar 

  • Price ER, Jin M, Lim D, Pati S, Walsh CT, McKeon FD . (1994). Cyclophilin B trafficking through the secretory pathway is altered by binding of cyclosporin A. Proc Natl Acad Sci USA 91: 3931–3935.

    Article  CAS  Google Scholar 

  • Pyrzynska B, Serrano M, Martinez AC, Kaminska B . (2002). Tumor suppressor p53 mediates apoptotic cell death triggered by cyclosporin A. J Biol Chem 277: 14102–14108.

    Article  CAS  Google Scholar 

  • Rey O, Baluda MA, Park NH . (1999). Differential gene expression in neoplastic and human papillomavirus-immortalized oral keratinocytes. Oncogene 18: 827–831.

    Article  CAS  Google Scholar 

  • Rippmann JF, Hobbie S, Daiber C, Guilliard B, Bauer M, Birk J et al. (2000). Phosphorylation-dependent proline isomerization catalyzed by Pin1 is essential for tumor cell survival and entry into mitosis. Cell Growth Differ 11: 409–416.

    CAS  PubMed  Google Scholar 

  • Ross HJ, Cho J, Osann K, Wong SF, Ramsinghani N, Williams J et al. (1997). Phase I/II trial of low dose cyclosporin A with EP for advanced non-small cell lung cancer. Lung Cancer 18: 189–198.

    Article  CAS  Google Scholar 

  • Scheibel T, Buchner J . (1998). The Hsp90 complex--a super-chaperone machine as a novel drug target. Biochem Pharmacol 56: 675–682.

    Article  CAS  Google Scholar 

  • Shevchenko A, Wilm M, Vorm O, Mann M . (1996). Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal Chem 68: 850–858.

    Article  CAS  Google Scholar 

  • Siddique M, Sabapathy K . (2006). Trp53-dependent DNA-repair is affected by the codon 72 polymorphism. Oncogene 25: 3489–3500.

    Article  CAS  Google Scholar 

  • Soe K, Hartmann H, Schlott B, Stevnsner T, Grosse F . (2002). The tumor suppressor protein p53 stimulates the formation of the human topoisomerase I double cleavage complex in vitro. Oncogene 21: 6614–6623.

    Article  CAS  Google Scholar 

  • Taylor WR, DePrimo SE, Agarwal A, Agarwal ML, Schonthal AH, Katula KS et al. (1999). Mechanisms of G2 arrest in response to overexpression of p53. Mol Biol Cell 10: 3607–3622.

    Article  CAS  Google Scholar 

  • Thomas M, Kalita A, Labrecque S, Pim D, Banks L, Matlashewski G . (1999). Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol 19: 1092–1100.

    Article  CAS  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ . (2000). Surfing the p53 network. Nature 408: 307–310.

    Article  CAS  Google Scholar 

  • Vousden KH, Lane DP . (2007). p53 in health and disease. Nat Rev Mol Cell Biol 8: 275–283.

    Article  CAS  Google Scholar 

  • Whitesell L, Sutphin PD, Pulcini EJ, Martinez JD, Cook PH . (1998). The physical association of multiple molecular chaperone proteins with mutant p53 is altered by geldanamycin, an hsp90-binding agent. Mol Cell Biol 18: 1517–1524.

    Article  CAS  Google Scholar 

  • Wulf G, Ryo A, Liou YC, Lu KP . (2003). The prolyl isomerase Pin1 in breast development and cancer. Breast Cancer Res 5: 76–82.

    Article  CAS  Google Scholar 

  • Wulf GM, Liou YC, Ryo A, Lee SW, Lu KP . (2002). The prolyl isomerase Pin1 in breast development and cancer. J Biol Chem 277: 47976–47979.

    Article  CAS  Google Scholar 

  • Yaffe MB, Schutkowski M, Shen M, Zhou XZ, Stukenberg PT, Rahfeld JU et al. (1997). Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science 278: 1957–1960.

    Article  CAS  Google Scholar 

  • Yang WM, Inouye CJ, Seto E . (1995). Cyclophilin A and FKBP12 interact with YY1 and alter its transcriptional activity. J Biol Chem 270: 15187–15193.

    Article  CAS  Google Scholar 

  • Zacchi P, Gostissa M, Uchida T, Salvagno C, Avolio F, Volinia S et al. (2002). The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 419: 853–857.

    Article  CAS  Google Scholar 

  • Zheng H, You H, Zhou XZ, Murray SA, Uchida T, Wulf G et al. (2002). The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 419: 849–853.

    Article  CAS  Google Scholar 

  • Zylicz M, King FW, Wawrzynow A . (2001). Hsp70 interactions with the p53 tumour suppressor protein. EMBO J 20: 4634–4638.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft grant GK1026 (to CS-F) and SFB604 (to Gunter Fischer, Halle, and FG). The technical assistance of Mrs Anita Willitzer is acknowledged. Jurkat cells were kindly provided by J Luban (Columbia University, New York).

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Authors and Affiliations

  1. Department of Biochemistry, Leibniz-Institute for Age Research (Fritz Lipmann Institute), Jena, Germany

    N Baum, F Grosse & B Schlott

  2. Max-Planck Research Unit for Protein Folding, Halle (Saale), Germany

    C Schiene-Fischer, M Frost & M Schumann

  3. Division of Cellular and Molecular Research, Laboratory of Molecular Carcinogenesis, National Cancer Centre, Singapore, Singapore

    K Sabapathy

  4. Department of NMR, Leibniz-Institute for Age Research, Jena, Germany

    O Ohlenschläger

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  1. N Baum
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Correspondence to B Schlott.

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

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Baum, N., Schiene-Fischer, C., Frost, M. et al. The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis. Oncogene 28, 3915–3925 (2009). https://doi.org/10.1038/onc.2009.248

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