Amino Acids

, Volume 41, Issue 4, pp 863–873 | Cite as

Evaluation of potential interactions between the metastasis-associated protein S100A4 and the tumor suppressor protein p53

  • Gisle BergeEmail author
  • Gunhild M. Mælandsmo
Review Article


Metastasis is a complex cascade of events involving a finely tuned interplay between malignant cells and multiple host factors. The transition from benign tumor growth to malignancy is manifested by the ability of tumor cells to traverse tissue barriers and invade surrounding tissues. Among a multitude of factors playing a role, the small calcium-binding protein S100A4 has been found to add to the invasive and metastatic capacity of cancer cells. However, the exact molecular function or mechanism by which S100A4 exerts its putative metastasis-promoting effects has not been fully elucidated, and the protein is most likely involved in several aspects of tumor progression. Several studies have recently described a direct interaction and/or reciprocal influence between S100A4 and the tumor suppressor protein p53. This corresponds to reports linking p53 to other S100-family members, especially S100B. The consequences are intriguing, connecting the metastasis-promoting protein S100A4 to the large set of important p53-mediated functions, with broad potential importance in cancer development and metastasis. In this review we emphasize the studies involving p53 and S100A4, elucidating and comparing reported results and conclusions.


S100 Protein Fluorescence Anisotropy Tetramerization Domain TP53 Mutational Status S100 Family Member 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to thank Dr. Kjetil Boye for critical reading of the manuscript. The present work was supported by a postdoctoral grant to Gisle Berge (Norwegian Cancer Society, grant number C99026) and the Program for Functional Genomics in the Norwegian Research Council (grant number 158954/S10).


  1. Ambartsumian NS, Grigorian MS, Larsen IF, Karlstrom O, Sidenius N, Rygaard J, Georgiev G, Lukanidin E (1996) Metastasis of mammary carcinomas in GRS/A hybrid mice transgenic for the mts1 gene. Oncogene 13:1621–1630PubMedGoogle Scholar
  2. Ambartsumian N, Klingelhofer J, Grigorian M, Christensen C, Kriajevska M, Tulchinsky E, Georgiev G, Berezin V, Bock E, Rygaard J, Cao R, Cao Y, Lukanidin E (2001) The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor. Oncogene 20:4685–4695. doi: 10.1038/sj.onc.1204636 PubMedCrossRefGoogle Scholar
  3. Andersen K, Maelandsmo GM, Hovig E, Fodstad O, Loennechen T, Winberg JO (1998) Interleukin-1 alpha and basic fibroblast growth factor induction of matrix metalloproteinases and their inhibitors in osteosarcoma cells is modulated by the metastasis associated protein CAPL. Anticancer Res 18:3299–3303PubMedGoogle Scholar
  4. Andersen K, Nesland JM, Holm R, Florenes VA, Fodstad O, Maelandsmo GM (2004) Expression of S100A4 combined with reduced E-cadherin expression predicts patient outcome in malignant melanoma. Mod Pathol 17:990–997. doi: 10.1038/modpathol.3800151 PubMedCrossRefGoogle Scholar
  5. Aylon Y, Oren M (2007) Living with p53, dying of p53. Cell 130:597–600. doi: 10.1016/j.cell.2007.08.005 PubMedCrossRefGoogle Scholar
  6. Baudier J, Delphin C, Grunwald D, Khochbin S, Lawrence JJ (1992) Characterization of the tumor suppressor protein p53 as a protein kinase C substrate and a S100b-binding protein. Proc Natl Acad Sci USA 89:11627–11631. doi: 10.1073/pnas.89.23.11627 PubMedCrossRefGoogle Scholar
  7. Berge G, Costea DE, Berg M, Rasmussen H, Grotterød I, Lothe RA, Mælandsmo GM, Flatmark K (2010) Coexpression and nuclear colocalization of metastasis-promoting protein S100A4 and p53 without mutual regulation in colorectal carcinoma. Amino Acids. doi: 10.1007/s00726-010-0514-6
  8. Bhattacharya S, Bunick CG, Chazin WJ (2004) Target selectivity in EF-hand calcium binding proteins. Biochim Biophys Acta 1742:69–79. doi: 10.1016/j.bbamcr.2004.09.002 PubMedCrossRefGoogle Scholar
  9. Bjornland K, Winberg JO, Odegaard OT, Hovig E, Loennechen T, Aasen AO, Fodstad O, Maelandsmo GM (1999) S100A4 involvement in metastasis: deregulation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in osteosarcoma cells transfected with an anti-S100A4 ribozyme. Cancer Res 59:4702–4708PubMedGoogle Scholar
  10. Boye K, Grotterod I, Aasheim HC, Hovig E, Maelandsmo GM (2008) Activation of NF-kappaB by extracellular S100A4: analysis of signal transduction mechanisms and identification of target genes. Int J Cancer 123:1301–1310. doi: 10.1002/ijc.23617 PubMedCrossRefGoogle Scholar
  11. Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, Dillehay L, Williams J, Lengauer C, Kinzler KW, Vogelstein B (1999) Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J Clin Invest 104:263–269. doi: 10.1172/JCI6863 PubMedCrossRefGoogle Scholar
  12. Chen H, Fernig DG, Rudland PS, Sparks A, Wilkinson MC, Barraclough R (2001) Binding to intracellular targets of the metastasis-inducing protein, S100A4 (p9Ka). Biochem Biophys Res Commun 286:1212–1217. doi: 10.1006/bbrc.2001.5517 PubMedCrossRefGoogle Scholar
  13. Chene P (2001) The role of tetramerization in p53 function. Oncogene 20:2611–2617. doi: 10.1038/sj.onc.1204373 PubMedCrossRefGoogle Scholar
  14. Daoud SS, Munson PJ, Reinhold W, Young L, Prabhu VV, Yu Q, LaRose J, Kohn KW, Weinstein JN, Pommier Y (2003) Impact of p53 knockout and topotecan treatment on gene expression profiles in human colon carcinoma cells: a pharmacogenomic study. Cancer Res 63:2782–2793PubMedGoogle Scholar
  15. Davies BR, Davies MP, Gibbs FE, Barraclough R, Rudland PS (1993) Induction of the metastatic phenotype by transfection of a benign rat mammary epithelial cell line with the gene for p9Ka, a rat calcium-binding protein, but not with the oncogene EJ-ras-1. Oncogene 8:999–1008PubMedGoogle Scholar
  16. Davies MP, Rudland PS, Robertson L, Parry EW, Jolicoeur P, Barraclough R (1996) Expression of the calcium-binding protein S100A4 (p9Ka) in MMTV-neu transgenic mice induces metastasis of mammary tumours. Oncogene 13:1631–1637PubMedGoogle Scholar
  17. De Petris L, Orre LM, Kanter L, Pernemalm M, Koyi H, Lewensohn R, Lehtio J (2008) Tumor expression of S100A6 correlates with survival of patients with stage I non-small-cell lung cancer. Lung Cancer 63:410–417. doi: 10.1016/j.lungcan.2008.06.003 PubMedCrossRefGoogle Scholar
  18. Delphin C, Ronjat M, Deloulme JC, Garin G, Debussche L, Higashimoto Y, Sakaguchi K, Baudier J (1999) Calcium-dependent interaction of S100B with the C-terminal domain of the tumor suppressor p53. J Biol Chem 274:10539–10544. doi: 10.1074/jbc.274.15.10539 PubMedCrossRefGoogle Scholar
  19. Donato R (1999) Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type. Biochim Biophys Acta 1450:191–231. doi: 10.1016/S0167-4889(99)00058-0 PubMedCrossRefGoogle Scholar
  20. Donato R (2003) Intracellular and extracellular roles of S100 proteins. Microsc Res Tech 60:540–551. doi: 10.1002/jemt.10296 PubMedCrossRefGoogle Scholar
  21. Dukhanina EA, Dukhanin AS, Lomonosov MY, Lukanidin EM, Georgiev GP (1997) Spectral studies on the calcium-binding properties of Mts1 protein and its interaction with target protein. FEBS Lett 410:403–406. doi: 10.1016/S0014-5793(97)00576-0 PubMedCrossRefGoogle Scholar
  22. Dulyaninova NG, Malashkevich VN, Almo SC, Bresnick AR (2005) Regulation of myosin-IIA assembly and Mts1 binding by heavy chain phosphorylation. Biochemistry 44:6867–6876. doi: 10.1021/bi0500776 PubMedCrossRefGoogle Scholar
  23. Dutta K, Cox CJ, Huang H, Basavappa R, Pascal SM (2002) Calcium coordination studies of the metastatic Mts1 protein. Biochemistry 41:4239–4245. doi: 10.1021/bi012061v PubMedCrossRefGoogle Scholar
  24. Dutta K, Cox CJ, Basavappa R, Pascal SM (2008) 15N relaxation studies of Apo-Mts1: a dynamic S100 protein. Biochemistry 47:7637–7647. doi: 10.1021/bi8005048 PubMedCrossRefGoogle Scholar
  25. EL Naaman C, Grum-Schwensen B, Mansouri A, Grigorian M, Santoni-Rugiu E, Hansen T, Kriajevska M, Schafer BW, Heizmann CW, Lukanidin E, Ambartsumian N (2004) Cancer predisposition in mice deficient for the metastasis-associated Mts1(S100A4) gene. Oncogene 23:3670–3680. doi: 10.1038/sj.onc.1207420 PubMedCrossRefGoogle Scholar
  26. Emberley ED, Murphy LC, Watson PH (2004) S100 proteins and their influence on pro-survival pathways in cancer. Biochem Cell Biol 82:508–515. doi: 10.1139/o04-052 PubMedCrossRefGoogle Scholar
  27. Endo H, Takenaga K, Kanno T, Satoh H, Mori S (2002) Methionine aminopeptidase 2 is a new target for the metastasis-associated protein, S100A4. J Biol Chem 277:26396–26402. doi: 10.1074/jbc.M202244200 PubMedCrossRefGoogle Scholar
  28. Fernandez-Fernandez MR, Veprintsev DB, Fersht AR (2005) Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor. Proc Natl Acad Sci USA 102:4735–4740. doi: 10.1073/pnas.0501459102 PubMedCrossRefGoogle Scholar
  29. Fernandez-Fernandez MR, Rutherford TJ, Fersht AR (2008) Members of the S100 family bind p53 in two distinct ways. Protein Sci 17:1663–1670. doi: 10.1110/ps.035527.108 PubMedCrossRefGoogle Scholar
  30. Flatmark K, Pedersen KB, Nesland JM, Rasmussen H, Aamodt G, Mikalsen SO, Bjornland K, Fodstad O, Maelandsmo GM (2003) Nuclear localization of the metastasis-related protein S100A4 correlates with tumour stage in colorectal cancer. J Pathol 200:589–595. doi: 10.1002/path.1381 PubMedCrossRefGoogle Scholar
  31. Florenes VA, Oyjord T, Holm R, Skrede M, Borresen AL, Nesland JM, Fodstad O (1994) TP53 allele loss, mutations and expression in malignant melanoma. Br J Cancer 69:253–259PubMedCrossRefGoogle Scholar
  32. Garbuglia M, Verzini M, Rustandi RR, Osterloh D, Weber DJ, Gerke V, Donato R (1999) Role of the C-terminal extension in the interaction of S100A1 with GFAP, tubulin, the S1. Biochem Biophys Res Commun 254:36–41. doi: 10.1006/bbrc.1998.9881 PubMedCrossRefGoogle Scholar
  33. Garrett SC, Varney KM, Weber DJ, Bresnick AR (2006) S100A4, a mediator of metastasis. J Biol Chem 281:677–680. doi: 10.1074/jbc.R500017200 PubMedCrossRefGoogle Scholar
  34. Giaccia AJ, Kastan MB (1998) The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev 12:2973–2983. doi: 10.1101/gad.12.19.2973 PubMedCrossRefGoogle Scholar
  35. Grigorian M, Ambartsumian N, Lykkesfeldt AE, Bastholm L, Elling F, Georgiev G, Lukanidin E (1996) Effect of mts1 (S100A4) expression on the progression of human breast cancer cells. Int J Cancer 67:831–841. doi: 10.1002/(SICI)1097-0215(19960917)67:6<831:AID-IJC13>3.0.CO;2-4 PubMedCrossRefGoogle Scholar
  36. Grigorian M, Andresen S, Tulchinsky E, Kriajevska M, Carlberg C, Kruse C, Cohn M, Ambartsumian N, Christensen A, Selivanova G, Lukanidin E (2001) Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. J Biol Chem 276:22699–22708. doi: 10.1074/jbc.M010231200 PubMedCrossRefGoogle Scholar
  37. Halazonetis TD, Kandil AN (1993) Conformational shifts propagate from the oligomerization domain of p53 to its tetrameric DNA binding domain and restore DNA binding to select p53 mutants. EMBO J 12:5057–5064PubMedGoogle Scholar
  38. Hamberg AP, Korse CM, Bonfrer JM, de Gast GC (2003) Serum S100B is suitable for prediction and monitoring of response to chemoimmunotherapy in metastatic malignant melanoma. Melanoma Res 13:45–49. doi: 10.1097/00008390-200302000-00008 PubMedCrossRefGoogle Scholar
  39. Haugen MH, Flatmark K, Mikalsen SO, Malandsmo GM (2008) The metastasis-associated protein S100A4 exists in several charged variants suggesting the presence of posttranslational modifications. BMC Cancer 8:172. doi: 10.1186/1471-2407-8-172 PubMedCrossRefGoogle Scholar
  40. Hauschild A, Michaelsen J, Brenner W, Rudolph P, Glaser R, Henze E, Christophers E (1999) Prognostic significance of serum S100B detection compared with routine blood parameters in advanced metastatic melanoma patients. Melanoma Res 9:155–161PubMedCrossRefGoogle Scholar
  41. Heizmann CW, Fritz G, Schafer BW (2002) S100 proteins: structure, functions and pathology. Front Biosci 7:d1356–d1368. doi: 10.2741/heizmann PubMedCrossRefGoogle Scholar
  42. Helfman DM, Kim EJ, Lukanidin E, Grigorian M (2005) The metastasis associated protein S100A4: role in tumour progression and metastasis. Br J Cancer 92:1955–1958. doi: 10.1038/sj.bjc.6602613 PubMedCrossRefGoogle Scholar
  43. Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T, Hovig E, Smith-Sorensen B, Montesano R, Harris CC (1994) Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res 22:3551–3555PubMedGoogle Scholar
  44. Hupp TR (1999) Regulation of p53 protein function through alterations in protein-folding pathways. Cell Mol Life Sci 55:88–95. doi: 10.1007/s000180050272 PubMedCrossRefGoogle Scholar
  45. Ikura M, Yap KL (2000) Where cancer meets calcium–p53 crosstalk with EF-hands. Nat Struct Biol 7:525–527. doi: 10.1038/76721 PubMedCrossRefGoogle Scholar
  46. Itahana Y, Ke H, Zhang Y (2008) p53 oligomerization is essential for its C-terminal lysine acetylation. J Biol Chem 284:5158–5164. doi: 10.1074/jbc.M805696200 PubMedCrossRefGoogle Scholar
  47. Joerger AC, Fersht AR (2008) Structural biology of the tumor suppressor p53. Annu Rev Biochem 77:557–582. doi: 10.1146/annurev.biochem.77.060806.091238 PubMedCrossRefGoogle Scholar
  48. Kikuchi N, Horiuchi A, Osada R, Imai T, Wang C, Chen X, Konishi I (2006) Nuclear expression of S100A4 is associated with aggressive behavior of epithelial ovarian carcinoma: an important autocrine/paracrine factor in tumor progression. Cancer Sci 97:1061–1069. doi: 10.1111/j.1349-7006.2006.00295.x PubMedCrossRefGoogle Scholar
  49. Klingelhofer J, Senolt L, Baslund B, Nielsen GH, Skibshoj I, Pavelka K, Neidhart M, Gay S, Ambartsumian N, Hansen BS, Petersen J, Lukanidin E, Grigorian M (2007) Up-regulation of metastasis-promoting S100A4 (Mts-1) in rheumatoid arthritis: putative involvement in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 56:779–789. doi: 10.1002/art.22398 PubMedCrossRefGoogle Scholar
  50. Kriajevska MV, Cardenas MN, Grigorian MS, Ambartsumian NS, Georgiev GP, Lukanidin EM (1994) Non-muscle myosin heavy chain as a possible target for protein encoded by metastasis-related mts-1 gene. J Biol Chem 269:19679–19682PubMedGoogle Scholar
  51. Kriajevska M, Tarabykina S, Bronstein I, Maitland N, Lomonosov M, Hansen K, Georgiev G, Lukanidin E (1998) Metastasis-associated Mts1 (S100A4) protein modulates protein kinase C phosphorylation of the heavy chain of nonmuscle myosin. J Biol Chem 273:9852–9856. doi: 10.1074/jbc.273.16.9852 PubMedCrossRefGoogle Scholar
  52. Kriajevska M, Fischer-Larsen M, Moertz E, Vorm O, Tulchinsky E, Grigorian M, Ambartsumian N, Lukanidin E (2002) Liprin beta 1, a member of the family of LAR transmembrane tyrosine phosphatase-interacting proteins, is a new target for the metastasis-associated protein S100A4 (Mts1). J Biol Chem 277:5229–5235. doi: 10.1074/jbc.M110976200 PubMedCrossRefGoogle Scholar
  53. Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331. doi: 10.1016/S0092-8674(00)81871-1 PubMedCrossRefGoogle Scholar
  54. Li ZH, Bresnick AR (2006) The S100A4 metastasis factor regulates cellular motility via a direct interaction with myosin-IIA. Cancer Res 66:5173–5180. doi: 10.1158/0008-5472.CAN-05-3087 PubMedCrossRefGoogle Scholar
  55. Li CL, Martinez V, He B, Lombet A, Perbal B (2002) A role for CCN3 (NOV) in calcium signalling. Mol Pathol 55:250–261. doi: 10.1136/mp.55.4.250 PubMedCrossRefGoogle Scholar
  56. Li ZH, Spektor A, Varlamova O, Bresnick AR (2003) Mts1 regulates the assembly of nonmuscle myosin-IIA. Biochemistry 42:14258–14266. doi: 10.1021/bi0354379 PubMedCrossRefGoogle Scholar
  57. Liang SH, Clarke MF (1999) The nuclear import of p53 is determined by the presence of a basic domain and its relative position to the nuclear localization signal. Oncogene 18:2163–2166. doi: 10.1038/sj.onc.1202350 PubMedCrossRefGoogle Scholar
  58. Liang SH, Clarke MF (2001) Regulation of p53 localization. Eur J Biochem 268:2779–2783. doi: 10.1046/j.1432-1327.2001.02227.x PubMedCrossRefGoogle Scholar
  59. Lin J, Blake M, Tang C, Zimmer D, Rustandi RR, Weber DJ, Carrier F (2001) Inhibition of p53 transcriptional activity by the S100B calcium-binding protein. J Biol Chem 276:35037–35041. doi: 10.1074/jbc.M104379200 PubMedCrossRefGoogle Scholar
  60. Lin J, Yang Q, Yan Z, Markowitz J, Wilder PT, Carrier F, Weber DJ (2004) Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells. J Biol Chem 279:34071–34077. doi: 10.1074/jbc.M405419200 PubMedCrossRefGoogle Scholar
  61. Maelandsmo GM, Hovig E, Skrede M, Engebraaten O, Florenes VA, Myklebost O, Grigorian M, Lukanidin E, Scanlon KJ, Fodstad O (1996) Reversal of the in vivo metastatic phenotype of human tumor cells by an anti-CAPL (mts1) ribozyme. Cancer Res 56:5490–5498PubMedGoogle Scholar
  62. Malashkevich VN, Varney KM, Garrett SC, Wilder PT, Knight D, Charpentier TH, Ramagopal UA, Almo SC, Weber DJ, Bresnick AR (2008) Structure of Ca(2+)-Bound S100A4 and its interaction with peptides derived from nonmuscle myosin-IIA. Biochemistry 47:5111–5126. doi: 10.1021/bi702537s PubMedCrossRefGoogle Scholar
  63. Malik S, Revington M, Smith SP, Shaw GS (2008) Analysis of the structure of human apo-S100B at low temperature indicates a unimodal conformational distribution is adopted by calcium-free S100 proteins. Proteins 73:28–42. doi: 10.1002/prot.22037 PubMedCrossRefGoogle Scholar
  64. Mandinova A, Atar D, Schafer BW, Spiess M, Aebi U, Heizmann CW (1998) Distinct subcellular localization of calcium binding S100 proteins in human smooth muscle cells and their relocation in response to rises in intracellular calcium. J Cell Sci 111(Pt 14):2043–2054PubMedGoogle Scholar
  65. Mann K, Hainaut P (2005) Aminothiol WR1065 induces differential gene expression in the presence of wild-type p53. Oncogene 24:3964–3975. doi: 10.1038/sj.onc.1208563 PubMedCrossRefGoogle Scholar
  66. Marenholz I, Heizmann CW, Fritz G (2004) S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun 322:1111–1122. doi: 10.1016/j.bbrc.2004.07.096 PubMedCrossRefGoogle Scholar
  67. Mathisen B, Lindstad RI, Hansen J, El Gewely SA, Maelandsmo GM, Hovig E, Fodstad O, Loennechen T, Winberg JO (2003) S100A4 regulates membrane induced activation of matrix metalloproteinase-2 in osteosarcoma cells. Clin Exp Metastasis 20:701–711. doi: 10.1023/B:CLIN.0000006819.21361.03 PubMedCrossRefGoogle Scholar
  68. Matsubara D, Niki T, Ishikawa S, Goto A, Ohara E, Yokomizo T, Heizmann CW, Aburatani H, Moriyama S, Moriyama H, Nishimura Y, Funata N, Fukayama M (2005) Differential expression of S100A2 and S100A4 in lung adenocarcinomas: clinicopathological significance, relationship to p53 and identification of their target genes. Cancer Sci 96:844–857. doi: 10.1111/j.1349-7006.2005.00121.x PubMedCrossRefGoogle Scholar
  69. Matsushima AY, Cesarman E, Chadburn A, Knowles DM (1994) Post-thymic T cell lymphomas frequently overexpress p53 protein but infrequently exhibit p53 gene mutations. Am J Pathol 144:573–584PubMedGoogle Scholar
  70. Moore BW (1965) A soluble protein characteristic of the nervous system. Biochem Biophys Res Commun 19:739–744. doi: 10.1016/0006-291X(65)90320-7 PubMedCrossRefGoogle Scholar
  71. Mueller A, Schafer BW, Ferrari S, Weibel M, Makek M, Hochli M, Heizmann CW (2005) The calcium-binding protein S100A2 interacts with p53 and modulates its transcriptional activity. J Biol Chem 280:29186–29193. doi: 10.1074/jbc.M505000200 PubMedCrossRefGoogle Scholar
  72. Novitskaya V, Grigorian M, Kriajevska M, Tarabykina S, Bronstein I, Berezin V, Bock E, Lukanidin E (2000) Oligomeric forms of the metastasis-related Mts1 (S100A4) protein stimulate neuronal differentiation in cultures of rat hippocampal neurons. J Biol Chem 275:41278–41286. doi: 10.1074/jbc.M007058200 PubMedCrossRefGoogle Scholar
  73. Orre LM, Pernemalm M, Lengqvist J, Lewensohn R, Lehtio J (2007) Upregulation, modification and translocation of S100A6 induced by exposure to ionizing radiation, revealed by proteomic profiling. Mol Cell Proteomics 6:2122–2131. doi: 10.1074/mcp.M700202-MCP200 PubMedCrossRefGoogle Scholar
  74. Oslejskova L, Grigorian M, Gay S, Neidhart M, Senolt L (2008) The metastasis associated protein S100A4: a potential novel link to inflammation and consequent aggressive behaviour of rheumatoid arthritis synovial fibroblasts. Ann Rheum Dis 67:1499–1504. doi: 10.1136/ard.2007.079905 PubMedCrossRefGoogle Scholar
  75. Parker C, Lakshmi MS, Piura B, Sherbet GV (1994) Metastasis-associated mts1 gene expression correlates with increased p53 detection in the B16 murine melanoma. DNA Cell Biol 13:343–351. doi: 10.1089/dna.1994.13.343 PubMedCrossRefGoogle Scholar
  76. Pathuri P, Vogeley L, Luecke H (2008) Crystal structure of metastasis-associated protein S100A4 in the active calcium-bound form. J Mol Biol 383:62–77. doi: 10.1016/j.jmb.2008.04.076 PubMedCrossRefGoogle Scholar
  77. Pedersen KB, Andersen K, Fodstad O, Maelandsmo GM (2004) Sensitization of interferon-gamma induced apoptosis in human osteosarcoma cells by extracellular S100A4. BMC Cancer 4:52. doi: 10.1186/1471-2407-4-52 PubMedCrossRefGoogle Scholar
  78. Poon GM, Brokx RD, Sung M, Gariepy J (2007) Tandem dimerization of the human p53 tetramerization domain stabilizes a primary dimer intermediate and dramatically enhances its oligomeric stability. J Mol Biol 365:1217–1231. doi: 10.1016/j.jmb.2006.10.051 PubMedCrossRefGoogle Scholar
  79. Rajagopalan S, Jaulent AM, Wells M, Veprintsev DB, Fersht AR (2008) 14-3-3 activation of DNA binding of p53 by enhancing its association into tetramers. Nucleic Acids Res 36:5983–5991. doi: 10.1093/nar/gkn598 PubMedCrossRefGoogle Scholar
  80. Rassidakis GZ, Thomaides A, Wang S, Jiang Y, Fourtouna A, Lai R, Medeiros LJ (2005) p53 gene mutations are uncommon but p53 is commonly expressed in anaplastic large-cell lymphoma. Leukemia 19:1663–1669. doi: 10.1038/sj.leu.2403840 PubMedCrossRefGoogle Scholar
  81. Rudland PS, Platt-Higgins A, Renshaw C, West CR, Winstanley JH, Robertson L, Barraclough R (2000) Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer. Cancer Res 60:1595–1603PubMedGoogle Scholar
  82. Rustandi RR, Drohat AC, Baldisseri DM, Wilder PT, Weber DJ (1998) The Ca(2+)-dependent interaction of S100B(beta beta) with a peptide derived from p53. Biochemistry 37:1951–1960. doi: 10.1021/bi972701n PubMedCrossRefGoogle Scholar
  83. Rustandi RR, Baldisseri DM, Weber DJ (2000) Structure of the negative regulatory domain of p53 bound to S100B(betabeta). Nat Struct Biol 7:570–574. doi: 10.1038/76797 PubMedCrossRefGoogle Scholar
  84. Salama I, Malone PS, Mihaimeed F, Jones JL (2008) A review of the S100 proteins in cancer. Eur J Surg Oncol 34:357–364. doi: 10.1016/j.ejso.2007.04.009 PubMedGoogle Scholar
  85. Saleem M, Kweon MH, Johnson JJ, Adhami VM, Elcheva I, Khan N, Bin HB, Bhat KM, Sarfaraz S, Reagan-Shaw S, Spiegelman VS, Setaluri V, Mukhtar H (2006) S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9. Proc Natl Acad Sci USA 103:14825–14830. doi: 10.1073/pnas.0606747103 PubMedCrossRefGoogle Scholar
  86. Santamaria-Kisiel L, Rintala-Dempsey AC, Shaw GS (2006) Calcium-dependent and -independent interactions of the S100 protein family. Biochem J 396:201–214. doi: 10.1042/BJ20060195 PubMedCrossRefGoogle Scholar
  87. Schmidt-Hansen B, Klingelhofer J, Grum-Schwensen B, Christensen A, Andresen S, Kruse C, Hansen T, Ambartsumian N, Lukanidin E, Grigorian M (2004a) Functional significance of metastasis-inducing S100A4(Mts1) in tumor-stroma interplay. J Biol Chem 279:24498–24504. doi: 10.1074/jbc.M400441200 PubMedCrossRefGoogle Scholar
  88. Schmidt-Hansen B, Ornas D, Grigorian M, Klingelhofer J, Tulchinsky E, Lukanidin E, Ambartsumian N (2004b) Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity. Oncogene 23:5487–5495. doi: 10.1038/sj.onc.1207720 PubMedCrossRefGoogle Scholar
  89. Schultz ES, Diepgen TL, Von Den DP (1998) Clinical and prognostic relevance of serum S-100 beta protein in malignant melanoma. Br J Dermatol 138:426–430. doi: 10.1046/j.1365-2133.1998.02119.x PubMedCrossRefGoogle Scholar
  90. Scotto C, Deloulme JC, Rousseau D, Chambaz E, Baudier J (1998) Calcium and S100B regulation of p53-dependent cell growth arrest and apoptosis. Mol Cell Biol 18:4272–4281PubMedGoogle Scholar
  91. Scotto C, Delphin C, Deloulme JC, Baudier J (1999) Concerted regulation of wild-type p53 nuclear accumulation and activation by S100B and calcium-dependent protein kinase C. Mol Cell Biol 19:7168–7180PubMedGoogle Scholar
  92. Semov A, Moreno MJ, Onichtchenko A, Abulrob A, Ball M, Ekiel I, Pietrzynski G, Stanimirovic D, Alakhov V (2005) Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin II and accelerated plasmin formation. J Biol Chem 280:20833–20841. doi: 10.1074/jbc.M412653200 PubMedCrossRefGoogle Scholar
  93. Senolt L, Grigorian M, Lukanidin E, Simmen B, Michel BA, Pavelka K, Gay RE, Gay S, Neidhart M (2006) S100A4 is expressed at site of invasion in rheumatoid arthritis synovium and modulates production of matrix metalloproteinases. Ann Rheum Dis 65:1645–1648. doi: 10.1136/ard.2005.047704 PubMedCrossRefGoogle Scholar
  94. Shaulsky G, Goldfinger N, Ben-Ze’ev A, Rotter V (1990) Nuclear accumulation of p53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. Mol Cell Biol 10:6565–6577PubMedGoogle Scholar
  95. Sherbet GV, Lakshmi MS (1998) S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis. Anticancer Res 18:2415–2421PubMedGoogle Scholar
  96. Slomnicki LP, Nawrot B, Lesniak W (2009) S100A6 binds p53 and affects its activity. Int J Biochem Cell Biol 41:784–790. doi: 10.1016/j.biocel.2008.08.007 PubMedCrossRefGoogle Scholar
  97. Soussi T (2007) p53 alterations in human cancer: more questions than answers. Oncogene 26:2145–2156. doi: 10.1038/sj.onc.1210280 PubMedCrossRefGoogle Scholar
  98. Soussi T, Beroud C (2001) Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer 1:233–240. doi: 10.1038/35106009 PubMedCrossRefGoogle Scholar
  99. Stommel JM, Marchenko ND, Jimenez GS, Moll UM, Hope TJ, Wahl GM (1999) A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J 18:1660–1672. doi: 10.1093/emboj/18.6.1660 PubMedCrossRefGoogle Scholar
  100. Takenaga K, Masuda A (1994) Restoration of microfilament bundle organization in v-raf-transformed NRK cells after transduction with tropomyosin 2 cDNA. Cancer Lett 87:47–53. doi: 10.1016/0304-3835(94)90408-1 PubMedCrossRefGoogle Scholar
  101. Takenaga K, Nakamura Y, Sakiyama S, Hasegawa Y, Sato K, Endo H (1994) Binding of pEL98 protein, an S100-related calcium-binding protein, to nonmuscle tropomyosin. J Cell Biol 124:757–768. doi: 10.1083/jcb.124.5.757 PubMedCrossRefGoogle Scholar
  102. Takenaga K, Nakamura Y, Sakiyama S (1997) Expression of antisense RNA to S100A4 gene encoding an S100-related calcium-binding protein suppresses metastatic potential of high-metastatic Lewis lung carcinoma cells. Oncogene 14:331–337. doi: 10.1038/sj.onc.1200820 PubMedCrossRefGoogle Scholar
  103. Tan M, Heizmann CW, Guan K, Schafer BW, Sun Y (1999) Transcriptional activation of the human S100A2 promoter by wild-type p53. FEBS Lett 445:265–268. doi: 10.1016/S0014-5793(99)00135-0 PubMedCrossRefGoogle Scholar
  104. Tarabykina S, Kriajevska M, Scott DJ, Hill TJ, Lafitte D, Derrick PJ, Dodson GG, Lukanidin E, Bronstein I (2000) Heterocomplex formation between metastasis-related protein S100A4 (Mts1) and S100A1 as revealed by the yeast two-hybrid system. FEBS Lett 475:187–191. doi: 10.1016/S0014-5793(00)01652-5 PubMedCrossRefGoogle Scholar
  105. Tarabykina S, Griffiths TR, Tulchinsky E, Mellon JK, Bronstein IB, Kriajevska M (2007) Metastasis-associated protein S100A4: spotlight on its role in cell migration. Curr Cancer Drug Targets 7:217–228. doi: 10.2174/156800907780618329 PubMedCrossRefGoogle Scholar
  106. van Dieck J, Fernandez-Fernandez MR, Verprintsev DB, Fersht AR (2009) Modulation of the oligomerization state of p53 by differential binding of proteins of the S100 family to p53 monomers and tetramers. J Biol Chem 284:13804–13811. doi: 10.1074/jbc.M901351200 PubMedCrossRefGoogle Scholar
  107. Wang G, Rudland PS, White MR, Barraclough R (2000) Interaction in vivo and in vitro of the metastasis-inducing S100 protein, S100A4 (p9Ka) with S100A1. J Biol Chem 275:11141–11146. doi: 10.1074/jbc.275.15.11141 PubMedCrossRefGoogle Scholar
  108. Weinberg RL, Veprintsev DB, Fersht AR (2004) Cooperative binding of tetrameric p53 to DNA. J Mol Biol 341:1145–1159. doi: 10.1016/j.jmb.2004.06.071 PubMedCrossRefGoogle Scholar
  109. Wilder PT, Rustandi RR, Drohat AC, Weber DJ (1998) S100B(betabeta) inhibits the protein kinase C-dependent phosphorylation of a peptide derived from p53 in a Ca2+-dependent manner. Protein Sci 7:794–798PubMedCrossRefGoogle Scholar
  110. Wilder PT, Lin J, Bair CL, Charpentier TH, Yang D, Liriano M, Varney KM, Lee A, Oppenheim AB, Adhya S, Carrier F, Weber DJ (2006) Recognition of the tumor suppressor protein p53 and other protein targets by the calcium-binding protein S100B. Biochim Biophys Acta 1763:1284–1297. doi: 10.1016/j.bbamcr.2006.08.024 PubMedCrossRefGoogle Scholar
  111. Zimmer DB, Wright SP, Weber DJ (2003) Molecular mechanisms of S100-target protein interactions. Microsc Res Tech 60:552–559. doi: 10.1002/jemt.10297 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium HospitalOslo University HospitalOsloNorway

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