Disease relevance of S100A2

• Our data suggest that in oral cancer cells the Ca(2+)- and cell cycle-dependent p53-S100A2 interaction might modulate proliferation [1].
• Interestingly, whereas none of the metastases expressed S100A2 mRNA, and the expression level was low in 6 cell lines established from primary melanomas, all nevi showed moderate to high expression levels [2].
• Our results suggest that loss of S100A2 gene expression may be an early event in melanoma development [2].
• The present work demonstrates a distinct intracellular localization of S100A6, S100A4, and S100A2 in two tumor cell lines derived from metastatic epithelial breast adenocarcinoma (MDA-MB231) and cervical carcinoma (HeLa) [3].
• OBJECTIVES: To characterize the disordered epithelial elements of pilomatrixoma by localizing S100A2, S100A3 and S100A6 proteins [4].
• These findings identify S100A2 as a strong metastasis inducer in vivo [5].

High impact information on S100A2

• CONCLUSION: Loss of S100A2 and increased expression of S100A4 may be an important event during progression of prostate cancer in humans [6].
• Tissue samples of BPH and prostatitis exhibited higher mRNA and protein levels of S100A2 than low-grade cancer (Gleason score <or= 6), whereas a complete loss was observed in high-grade cancer specimens (Gleason score > 6) [6].
• Positive immunohistochemical staining of S100A2 was detected in the majority (75-83%) of normal and hyperplastic lung tissues, whereas it was detected in <10% of metaplastic lung tissues, squamous cell carcinoma, and adenocarcinoma [7].
• Treatment of 1170-I HBE and NSCLC cells with 5-aza-2'-deoxycytidine resulted in partial restoration of S100A2 expression in seven of eight cell lines [7].
• Indeed, CpG methylation was detected in the promoter region of the S100A2 gene [7].

Chemical compound and disease context of S100A2

• METHODS: The promoter and exon 1 region of the S100A6 and S100A2 genes was sequenced in bisulfite modified DNA from non-malignant, benign prostatic hyperplasia (BPH), malignant and metastatic prostate tissues and in cell lines [8].

Biological context of S100A2

• Finally, luciferase-coupled transactivation assays, where a p53-reporter construct was used, indicated that interaction with S100A2 increased p53 transcriptional activity [1].
• The results showed an upregulation of S100A2 protein in atypical keratinocytes in PAK and in normal keratinocytes adjacent to melanoma cells in LM [9].
• CaN19 (S100A2), a member of the S100 family of calcium-binding proteins, was originally isolated in a screen for tumor suppressor genes [10].
• Among these, S100A2 has recently attracted major interest due to its stable expression in normal epithelia and down-regulation in some tumors [11].
• S100A2 is a Ca(2+)-binding EF-hand protein that is mainly localized in the nucleus [12].

Anatomical context of S100A2

• Subtractive hybridization of tumorigenic versus normal tumor-derived mammary epithelial cells has previously identified the S100A2 protein as potential tumor suppressor [1].
• In human smooth muscle cells, which co-express S100A2 in the nucleus and S100A1 in stress fibers, S100A13 shows a unique subcellular localization in the perinuclear area [13].
• In contrast, S100A2 was located primarily in the cell nucleus [14].
• The S100A2 antibody stained the basal layer of the epidermis and hair follicles of normal skin [15].
• Expression and prognostic significance of S100A2 protein in squamous cell carcinoma of the esophagus [11].

Associations of S100A2 with chemical compounds

• Here, we report for the first time that during recovery from hydroxyurea treatment, the S100A2 protein translocated from the cytoplasm to the nucleus and co-localized with the tumor suppressor p53 in two different oral carcinoma cells (FADU and SCC-25) [1].
• Human S100A2 contains four cysteine residues, each of them located at positions that may be important for Zn(2+) binding [16].
• Here we show that Cys(1(3)) (the number in parentheses indicating the position in the sequence of S100A2) is the crucial determinant for Zn(2+) binding in association with conformational changes as determined by internal tyrosine fluorescence [16].
• Of note, p53 family members do not trigger S100A2 gene expression in response to apoptotic doses of cisplatin and doxorubicin [17].
• This phenomenon, consistent with translocation of S100A2 from the nucleus to the cytoplasm, could also be induced in normal human keratinocytes by increasing intracellular Ca2+ levels with the ionophore A23187 [18].

Physical interactions of S100A2

• Preliminary characterization of this interaction indicated that the region in p53 involved with binding to S100A2 is located at the C terminus of p53 [1].

Co-localisations of S100A2

• We also investigated whether S100A2 could be co-localized with cytokeratin K14, an intermediate filament protein expressed in basal proliferative keratinocytes [19].

Regulatory relationships of S100A2

• EGF stimulates transcription of CaN19 (S100A2) in HaCaT keratinocytes [10].
• Thus, p53 appears to positively regulate S100A2 expression [20].
• The antiproliferative activity of S100A2 is significantly enhanced by IFN-alpha in stably transfected ME15 or D10 cell lines [21].

Other interactions of S100A2

• While the S100A5 protein was significantly expressed in all the astrocytic tumors (but without any significant modifications in the levels of malignancy), the S100A2 protein was never expressed in these tumors [22].
• Differential expression patterns of S100A2, S100A4 and S100A6 during progression of human malignant melanoma [2].
• S100A1 and S100A3 antibodies are not expressed in melanocytic lesions and S100A2 is only found in selected tumours [15].
• DSG3 was expressed in association with the cell membrane of the basal and suprabasal epithelial cells, and S100A2 was expressed in the nucleus and cytoplasm, often as intracellular granules [23].
• The high transcription of TACSTD2 and S100A2 in PL16T was confirmed by in situ hybridization [24].

Analytical, diagnostic and therapeutic context of S100A2

• Quantitative real-time PCR on primary GC samples demonstrated overexpression of S100A2 in 18 of 20 tumors (90%) [25].
• Co-immunoprecipitation experiments and electrophoretic mobility shift assay showed that the interaction between S100A2 and p53 is Ca(2+)-dependent [1].
• The DSG3, S100A2, and SLPI proteins were quantified by Western blotting, and the cellular localization was determined by immunohistochemistry [23].
• Oligonucleotide array, quantitative reverse transcription-polymerase chain reaction and western blot analyses of lung adenocarcinoma cell lines and bronchiolar epithelial cells (SAEC and NHBE) revealed that S100A2 and S100A4 were the most strikingly downregulated and upregulated members of the S100 family, respectively [26].
• Mapping the zinc ligands of S100A2 by site-directed mutagenesis [16].

References