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

• Using this model we demonstrate that systemic therapy with cyclophosphamide or dacarbazine can produce metastatic cell killing consistent with complete eradication of established pulmonary metastases [11].
• Direct antiproliferative effects of melatonin on two metastatic cell sublines of mouse melanoma (B16BL6 and PG19) [12].
• In order to test the effect of Cicaprost on lymphogenous metastasis we chose the metastatic cell clone MTLn3 derived from the 13762NF rat mammary carcinoma [13].

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

• In serum-stimulated fibroblasts, the increase in 18A2 mRNA is dependent on protein synthesis [15].
• A variety of mouse tissues express the 18A2 mRNA, with the highest levels detected in the non-pregnant uterus and in the placenta [15].
• The S100-related calcium-binding protein S100A4 (p9Ka) is expressed at a low level in rat mammary epithelial cells from normal mammary gland and benign mammary tumors [18].
• Nontransgenic littermates expressed the Mts1 protein only in the stromal cells surrounding the tumor but not in the tumor cells by itself [19].
• We found by double immunostaining with a macrophage-specific antibody that Mts1 protein was highly expressed in fetal macrophages throughout the embryonic mesenchyme and in macrophages colonizing developing lymphatic and non-lymphatic organs [20].

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

• Mts1 protein can interact with non-muscle myosin, indicating that Mts1 plays a role in cell motility [20].

Regulatory relationships of S100a4

• The present results suggest that metastasin-induced invasiveness of several malignant tumor cells is at least partially caused by down-regulation of E-cadherin [26].
• We previously reported that ras-transformed NIH 3T3 cells could be selected in vivo for increased metastatic ability after intravenous injection into chick embryos, and that the metastatic cell populations expressed increased levels of ras p21 protein [27].
• Cytoskeletal visualization by immunofluorescence staining revealed that the tumorigenic and metastatic cell lines expressed an altered organization of actin cables and a smaller number of vinculin-containing focal contacts [28].
• Experiments showed that metastasin-induced activation of Ca-ATPase is a possible mechanisms of CSML-100 cell resistance to cytolytic dexamethasone action [29].

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

• Here we follow chemical shift changes which occur in Mts1 upon titration of calcium [1].
• Pulmonary lesions can be detected using a simple bioassay procedure which is useful for estimation of metastatic cell killing [11].
• Five strongly metastatic and 5 weakly metastatic cell clones from a murine fibrosarcoma were examined for the occurrence of both cell-surface moieties by immunofluorescence flow cytometry and microscopy [31].
• In a methylcholanthrene-induced tumor (MCA-F) model in C3H/HeJ mice, curative resection of a progressive tumor promotes artificial lung metastases following intravenous injection of a highly metastatic cell variant designated clone 9-4 [32].
• However, all diets containing CLA significantly decreased the total tumor burden (volume of tumor, mm(3)) in lungs of mice from both spontaneous metastasis (reduced by 42-73%) as well as implantation and survival of the metastatic cell (reduced by 46-61%) when compared with diets containing no CLA [33].

References