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Gene Review

S100a4  -  S100 calcium binding protein A4

Mus musculus

Synonyms: 18A2, 42a, CAPL, Capl, FSp1, ...
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Disease relevance of S100a4

  • Mts1, also known as S100A4, is an 11 kDa calcium-binding protein strongly linked to metastasis [1].
  • These constructs were analyzed in transient transfection assays in two related cell lines derived from mouse mammary adenosarcomas: CSML-0, a nonmetastatic cell line with low levels of mts1 expression, and CSML-100, a metastatic cell line with high levels of mts1 expression [2].
  • This sequence element was able to form several sequence-specific complexes with nuclear proteins extracted from both Mts1-expressing CSML100 and Mts1-non-expressing CSML0 adenocarcinoma cells [3].
  • Elevated levels of the calcium-binding protein S100A4 have been causally linked to the metastatic spread of breast cancer cells in several in vitro and in vivo model systems and, more recently, correlated with patient death in a series of human breast cancer specimens [4].
  • The structure and the function of the p53 gene were studied in two metastatic cell variants derived from Lewis lung carcinoma [5].

High impact information on S100a4

  • We demonstrate that loss of RhoC does not affect tumor development but decreases tumor cell motility and metastatic cell survival leading to a drastic inhibition of metastasis [6].
  • DNA sequencing of mts1 revealed an open reading frame containing information for a peptide of 101 amino acids, and the amino acid sequence suggested that the mts1 protein was identical to the previously isolated Ca2+-binding mouse protein (Jackson-Grusby et al. 1987; Goto et al. 1988) [7].
  • CAPL transcripts are present in several classes of identified neurons containing transmitter-sensitive adenylate cyclase, including sensory cells, bag cells, and the left pleural giant cell [8].
  • Chronic activation of the phosphoinositide 3-kinase (PI3K)/PTEN signal transduction pathway contributes to metastatic cell growth, but up to now effectors mediating this response are poorly defined [9].
  • We previously showed that the calcium-binding protein S100A4 is overexpressed during the progression of prostate cancer (CaP) in humans and in the TRAMP (transgenic adenocarcinoma of the mouse prostate) mouse model [10].

Chemical compound and disease context of S100a4


Biological context of S100a4

  • Here, we followed an outcross/backcross breeding strategy in conjunction with genotyping for microsatellites and a novel marker for the gene S100a4 [14].
  • The concentration of 18A2 mRNA in total placental RNA decreases from day 8 to day 10 of pregnancy, and is below detection throughout the latter half of gestation [15].
  • As a member of the S100 protein family, Mts1 is predicted to contain four alpha-helices and two calcium-binding loops, the second of which forms a canonical EF hand, while the first is a pseudo-EF hand, using two extra residues and principally backbone carbonyls rather than side chain oxygens to coordinate calcium [1].
  • Cacy is shown to be within 8 kb of Capl in the mouse genome [16].
  • Some genes with expression known to be regulated by promoter methylation were suppressed in Pemt knockout brain (such as S100a4 and TP53) [17].

Anatomical context of S100a4


Associations of S100a4 with chemical compounds

  • Partial amino acid sequence analysis of the purified 10-kD protein, two-dimensional polyacrylamide gel analysis and a binding experiment revealed that the 10-kD protein was identical to a calcium-binding protein derived from mRNA named pEL98 or 18A2 that is homologous to S100 protein [21].
  • Furthermore, association between myosin and Mts-1 was confirmed by sucrose gradient analysis [22].
  • Two calcium-binding sites of the Mts1 protein, a member of S-100 protein family, were distinguished with the Fluo-3 fluorescent technique [23].
  • Cathepsin B to cysteine proteinase inhibitor balance in metastatic cell subpopulations isolated from murine tumors [24].
  • This proline-domain conformation may suggest a collagen type IV receptor-specific, metastatic cell adhesion promoting binding domain [25].

Physical interactions of S100a4


Regulatory relationships of S100a4


Other interactions of S100a4

  • The 18A2 mRNA is similar in size, serum-inducibility, and sequence to the 2A9 mRNA (1), but these mRNAs are derived from distinct genes [15].
  • We found that hsh is flanked between D3Mit187 proximally and S100a4 distally [14].
  • Wild-type p53 differentially affects tumorigenic and metastatic potential of murine metastatic cell variants [5].
  • Because E-cadherin is an invasion suppressor molecule, and metastasin a metastasis-inducing molecule, we wondered which molecule was playing a dominant role in the balance that finally leads to noninvasiveness or invasiveness [26].
  • Expression of Mts1, a metastasis-associated gene, increases motility but not invasion of a nonmetastatic mouse mammary adenocarcinoma cell line [30].

Analytical, diagnostic and therapeutic context of S100a4


  1. Calcium coordination studies of the metastatic Mts1 protein. Dutta, K., Cox, C.J., Huang, H., Basavappa, R., Pascal, S.M. Biochemistry (2002) [Pubmed]
  2. Transcriptional analysis of the mts1 gene with specific reference to 5' flanking sequences. Tulchinsky, E., Ford, H.L., Kramerov, D., Reshetnyak, E., Grigorian, M., Zain, S., Lukanidin, E. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  3. A kappaB-related binding site is an integral part of the mts1 gene composite enhancer element located in the first intron of the gene. Tulchinsky, E., Prokhortchouk, E., Georgiev, G., Lukanidin, E. J. Biol. Chem. (1997) [Pubmed]
  4. Examination of tumour histopathology and gene expression in a neu/S100A4 transgenic model of metastatic breast cancer. Simpson, P.T., Shoker, B.S., Barraclough, R., Halliwell, N., Rudland, P.S., Sibson, D.R., Davies, M.P. International journal of experimental pathology. (2003) [Pubmed]
  5. Wild-type p53 differentially affects tumorigenic and metastatic potential of murine metastatic cell variants. Rizzo, M.G., Soddu, S., Tibursi, G., Calabretta, B., Sacchi, A. Clin. Exp. Metastasis (1993) [Pubmed]
  6. RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis. Hakem, A., Sanchez-Sweatman, O., You-Ten, A., Duncan, G., Wakeham, A., Khokha, R., Mak, T.W. Genes Dev. (2005) [Pubmed]
  7. Isolation and characterization of a gene specifically expressed in different metastatic cells and whose deduced gene product has a high degree of homology to a Ca2+-binding protein family. Ebralidze, A., Tulchinsky, E., Grigorian, M., Afanasyeva, A., Senin, V., Revazova, E., Lukanidin, E. Genes Dev. (1989) [Pubmed]
  8. Two catalytic subunits of cAMP-dependent protein kinase generated by alternative RNA splicing are expressed in Aplysia neurons. Beushausen, S., Bergold, P., Sturner, S., Elste, A., Roytenberg, V., Schwartz, J.H., Bayley, H. Neuron (1988) [Pubmed]
  9. PKN3 is required for malignant prostate cell growth downstream of activated PI 3-kinase. Leenders, F., Möpert, K., Schmiedeknecht, A., Santel, A., Czauderna, F., Aleku, M., Penschuck, S., Dames, S., Sternberger, M., Röhl, T., Wellmann, A., Arnold, W., Giese, K., Kaufmann, J., Klippel, A. EMBO J. (2004) [Pubmed]
  10. S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9. Saleem, M., Kweon, M.H., Johnson, J.J., Adhami, V.M., Elcheva, I., Khan, N., Bin Hafeez, B., Bhat, K.M., Sarfaraz, S., Reagan-Shaw, S., Spiegelman, V.S., Setaluri, V., Mukhtar, H. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  11. Practical spontaneous metastasis model for in vivo therapeutic studies using a human melanoma. Shoemaker, R.H., Dykes, D.J., Plowman, J., Harrison, S.D., Griswold, D.P., Abbott, B.J., Mayo, J.G., Fodstad, O., Boyd, M.R. Cancer Res. (1991) [Pubmed]
  12. Direct antiproliferative effects of melatonin on two metastatic cell sublines of mouse melanoma (B16BL6 and PG19). Cos, S., Garcia-Bolado, A., Sánchez-Barceló, E.J. Melanoma Res. (2001) [Pubmed]
  13. The stable prostacyclin analogue Cicaprost inhibits metastasis to lungs and lymph nodes in the 13762NF MTLn3 rat mammary carcinoma. Schirner, M., Lichtner, R.B., Schneider, M.R. Clin. Exp. Metastasis (1994) [Pubmed]
  14. Mapping of the dysmyelinating murine Hindshaker mutation to a 1.2-cM interval on chromosome 3. Vouyiouklis, D.A., Anderson, T.J., King, H.E., Kirkham, D., Karim, S.A., Johnson, K.J., Griffiths, I.R. Genomics (2002) [Pubmed]
  15. A growth-related mRNA in cultured mouse cells encodes a placental calcium binding protein. Jackson-Grusby, L.L., Swiergiel, J., Linzer, D.I. Nucleic Acids Res. (1987) [Pubmed]
  16. Related calcium-binding proteins map to the same subregion of chromosome 1q and to an extended region of synteny on mouse chromosome 3. Dorin, J.R., Emslie, E., van Heyningen, V. Genomics (1990) [Pubmed]
  17. Gene expression profiling in phosphatidylethanolamine N-methyltransferase knockout mice. Zhu, X., Zeisel, S.H. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  18. Transcriptional down-regulation of the metastasis-inducing S100A4 (p9Ka) in benign but not in malignant rat mammary epithelial cells by GC-factor. Chen, D., Davies, M.P., Rudland, P.S., Barraclough, R. J. Biol. Chem. (1997) [Pubmed]
  19. Metastasis of mammary carcinomas in GRS/A hybrid mice transgenic for the mts1 gene. Ambartsumian, N.S., Grigorian, M.S., Larsen, I.F., Karlstrøm, O., Sidenius, N., Rygaard, J., Georgiev, G., Lukanidin, E. Oncogene (1996) [Pubmed]
  20. Expression of the metastasis-associated mts1 gene during mouse development. Klingelhöfer, J., Ambartsumian, N.S., Lukanidin, E.M. Dev. Dyn. (1997) [Pubmed]
  21. Binding of pEL98 protein, an S100-related calcium-binding protein, to nonmuscle tropomyosin. Takenaga, K., Nakamura, Y., Sakiyama, S., Hasegawa, Y., Sato, K., Endo, H. J. Cell Biol. (1994) [Pubmed]
  22. Non-muscle myosin heavy chain as a possible target for protein encoded by metastasis-related mts-1 gene. Kriajevska, M.V., Cardenas, M.N., Grigorian, M.S., Ambartsumian, N.S., Georgiev, G.P., Lukanidin, E.M. J. Biol. Chem. (1994) [Pubmed]
  23. Spectral studies on the calcium-binding properties of Mts1 protein and its interaction with target protein. Dukhanina, E.A., Dukhanin, A.S., Lomonosov, M.Y., Lukanidin, E.M., Georgiev, G.P. FEBS Lett. (1997) [Pubmed]
  24. Cathepsin B to cysteine proteinase inhibitor balance in metastatic cell subpopulations isolated from murine tumors. Rozhin, J., Gomez, A.P., Ziegler, G.H., Nelson, K.K., Chang, Y.S., Fong, D., Onoda, J.M., Honn, K.V., Sloane, B.F. Cancer Res. (1990) [Pubmed]
  25. Cell adhesion promoting peptide GVKGDKGNPGWPGAP from the collagen type IV triple helix: cis/trans proline-induced multiple 1H NMR conformations and evidence for a KG/PG multiple turn repeat motif in the all-trans proline state. Mayo, K.H., Parra-Diaz, D., McCarthy, J.B., Chelberg, M. Biochemistry (1991) [Pubmed]
  26. E-cadherin and metastasin (mts-1/S100A4) expression levels are inversely regulated in two tumor cell families. Keirsebilck, A., Bonné, S., Bruyneel, E., Vermassen, P., Lukanidin, E., Mareel, M., van Roy, F. Cancer Res. (1998) [Pubmed]
  27. ras-transformed NIH 3T3 cell lines, selected for metastatic ability in chick embryos, have increased proportions of p21-expressing cells and are metastatic in nude mice. Chambers, A.F., Denhardt, G.H., Wilson, S.M. Invasion Metastasis (1990) [Pubmed]
  28. The establishment and characterization of a new BALB/c angiosarcoma tumor system. Zvibel, I., Raz, A. Int. J. Cancer (1985) [Pubmed]
  29. Molecular mechanisms of different sensitivity of tumor cells to dexamethasone. Dukhanin, A.S., Romanova, E.A., Dukhanina, E.A. Bull. Exp. Biol. Med. (2001) [Pubmed]
  30. Expression of Mts1, a metastasis-associated gene, increases motility but not invasion of a nonmetastatic mouse mammary adenocarcinoma cell line. Ford, H.L., Salim, M.M., Chakravarty, R., Aluiddin, V., Zain, S.B. Oncogene (1995) [Pubmed]
  31. Cell-surface laminin-like molecules and alpha-D-galactopyranosyl end-groups of cloned strongly and weakly metastatic murine fibrosarcoma cells. Grimstad, I.A., Bosnes, V. Int. J. Cancer (1987) [Pubmed]
  32. Antigen-specific therapy of experimental metastases. Nomi, S., Pellis, N.R., Kahan, B.D. Cancer (1985) [Pubmed]
  33. Effect of separate conjugated linoleic acid isomers on murine mammary tumorigenesis. Hubbard, N.E., Lim, D., Erickson, K.L. Cancer Lett. (2003) [Pubmed]
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