Alternative titles; symbols
HGNC Approved Gene Symbol: TFF1
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38): 21:42,362,282-42,366,535 (from NCBI)
Trefoil proteins, such as TTF1, are stable secretory polypeptides that are characterized by the presence of at least 1 copy of a 40-amino acid motif that contains 3 conserved disulfide bonds.
Jakowlew et al. (1984) presented the complete nucleotide sequence of a human pS2 cDNA isolated from the human breast cancer cell line MCF-7. The predicted protein has 84 amino acids.
By Northern blot analysis, Tomasetto et al. (1990) found that both pS2 and SP are expressed in normal human stomach epithelium. They noted that pS2 mRNA and protein expression are detected in approximately 50% of human breast tumors. Hanby et al. (1993) found that human pS2 and SP mRNAs and pS2 peptide are colocalized in the gastric foveolar and surface epithelium throughout the stomach. Based on the distribution of pS2 and SP, the authors suggested that both may be involved in repair-enhancing mechanisms.
Using a combination of RT-PCR and rapid amplification of cDNA ends, Itoh et al. (1996) cloned and sequenced a rat pS2 cDNA from stomach. The deduced amino acid sequence is very similar to those of the human and mouse pS2 proteins. However, except for the well-conserved cysteine residues of the trefoil motif, this amino acid sequence is very different from those of other rat trefoil peptides, such as SP (Tff2) and intestinal trefoil factor (Itf, or Tff3). Northern blotting showed that rat pS2 is expressed in the stomach and duodenum but not in the distal small intestine, large intestine, rectum, brain, liver, testis, or other tissues.
Roberts et al. (1988) demonstrated that the pS2 gene is transcriptionally induced in MCF-7 cells by estrogen. The 5-prime flanking sequence from -3000 to +10 basepairs appeared to act as an estrogen-inducible promoter in the system used by Roberts et al. (1988).
Using chromatin immunoprecipitation assays, Metivier et al. (2003) identified protein complexes recruited by ESR1 (133430) to the pS2 promoter in a breast carcinoma cell line following estradiol treatment, and they determined the order in which the complexes were recruited.
Itoh et al. (1996) examined the expression of rat pS2, rat SP, and rat Itf during the course of acetic acid-induced colitis. They detected pS2 mRNA during the acute phase of colitis but not during recovery or in normal controls.
By combining conventional biochemical methods with mass spectrometry, Chutipongtanate et al. (2005) found that TFF1 in normal human urine inhibited the growth of calcium oxalate crystals. Urinary TFF1 showed an inhibitory potency similar to that of nephrocalcin, and inhibition was dose dependent and inhibited by TFF1 antisera, particularly by antisera directed to the TFF1 C terminus. Concentrations and relative amounts of TFF1 in the urine of patients with idiopathic calcium oxalate kidney stones were significantly less than those found in controls. Chutipongtanate et al. (2005) proposed a model whereby 4 C-terminal glutamic residues of TFF1 interact with calcium ions to prevent calcium oxalate crystal growth.
Metivier et al. (2008) presented evidence of an unanticipated dynamic role for DNA methylation in gene regulation in human cells. Periodic, strand-specific methylation/demethylation occurs during transcriptional cycling of the pS2/TFF1 gene promoter on activation by estrogens. DNA methyltransferases exhibit dual actions during these cycles, being involved in CpG methylation and active demethylation of (5m)CpGs through deamination. Inhibition of this process precludes demethylation of the pS2 gene promoter and its subsequent transcriptional activation. Metivier et al. (2008) concluded that cyclic changes in the methylation status of promoter CpGs may thus represent a critical event in transcriptional achievement.
Kangaspeska et al. (2008) independently showed that cyclic methylation and demethylation of CpG dinucleotides, with a periodicity of around 100 minutes, is characteristic for 5 selected promoters, including the estrogen (E2)-responsive pS2 gene, in human cells. When the pS2 gene was actively transcribed, DNA methylation occurred after the cyclic occupancy of the estrogen receptor-alpha (ESRA; 133430) and RNA polymerase II (see 180660). Moreover, Kangaspeska et al. (2008) reported conditions that provoked methylation cycling of the pS2 promoter in cell lines in which pS2 expression was quiescent and the proximal promoter was methylated. This coincided with a low level reexpression of ER-alpha and of pS2 transcripts.
Jeltsch et al. (1987) reported that the human pS2 gene is composed of 3 exons spanning less than 5 kb.
The BCEI gene was assigned to chromosome 21 (Cohen-Haguenauer et al., 1985; Moisan et al., 1985). Furthermore, Moisan et al. (1985) showed by in situ hybridization that the gene is located in the segment 21q22.3, which is the critical segment in Down syndrome. They also demonstrated a RFLP with BamHI. Moisan et al. (1988) mapped the gene to chromosome 21 using a panel of somatic cell hybrid lines. They described a BstE2 RFLP. Watkins et al. (1987) found that the BCEI gene is closely linked to 2 DNA markers located at 21q22.3 (theta = 0.0 with high lod scores for both).
Seib et al. (1997) found that the pS2, TFF2 (182590), and TFF3 (600633) genes are clustered within a region spanning 55 kb. May and Westley (1997) determined that the physical distance between the TFF1 and TFF2 genes is only 12.5 kb. It appears likely that these 2 genes arose by gene duplication. The TFF1 and TFF2 genes have similar patterns of expression, suggesting that they may share common regulatory elements.
In order to elucidate the function of the pS2 trefoil peptide, which is normally expressed in gastric mucosa and occurs in the epithelial cell cytoplasm, Lefebvre et al. (1996) disrupted the mouse pS2 gene by homologous recombination. They demonstrated that mpS2 +/+ mice and mpS29 +/- mice expressed high and intermediate levels of mpS2 protein, respectively, whereas mpS -/- mice showed no detectable expression. When interbred, the mpS2 -/- mice were fertile and there was no evidence of embryonic lethality. Histologic examination of tissues from mpS2 -/- mice revealed that organs were normal, except for the stomach. In 3-week-old pups, the antral and pyloric mucosa were thicker. At 5 months, all examined mPS2 -/- mice exhibited circumferential adenoma encompassing the whole antropyloric mucosa. The epithelial cells lining the surface and the elongated mucosal pits showed high-grade dysplasia. In 30% of 5-month-old mpS2 -/- mice, 2 to 5 foci of carcinoma were observed within the adenoma. Histologic findings were characteristic of intraepithelial and intramucosal carcinoma. Lefebvre et al. (1996) reported that the lamina propria (LP) in the small intestine of mpS2 -/- mice was thickened and contained inflammatory cells. Epithelial cells lining the intestinal villi were normal. The authors suggested that the pS2 protein may exert a protective function and that its absence may lead to intestine mucosal barrier defects accompanied by a local lymphoproliferative response. Since all mpS2 -/- mice developed gastric adenoma, but only 30% developed gastric carcinoma, Lefebvre et al. (1996) concluded that the loss of pS2 protein may not be sufficient for malignancy. They noted that about 50% of human gastric carcinomas have lost expression of pS2 and that aberrant pS2 transcripts have been isolated from gastric carcinomas.
Chutipongtanate, S., Nakagawa, Y., Sritippayawan, S., Pittayamateekul, J., Parichatikanond, P., Westley, B. R., May, F. E. B., Malasit, P., Thongboonkerd, V. Identification of human urinary trefoil factor 1 as a novel calcium oxalate crystal growth inhibitor. J. Clin. Invest. 115: 3613-3622, 2005. [PubMed: 16308573] [Full Text: https://doi.org/10.1172/JCI25342]
Cohen-Haguenauer, O., Van Cong, N., Prud'homme, J. F., Jegou-Foubert, C., Gross, M. S., De Tand, M. F., Milgrom, E., Frezal, J. A gene expressed in human breast cancer and regulated by estrogen in MCF-7 cells is located on chromosome 21. (Abstract) Cytogenet. Cell Genet. 40: 606 only, 1985.
Hanby, A. M., Poulsom, R., Singh, S., Elia, G., Jeffery, R. E., Wright, N. A. Spasmolytic polypeptide is a major antral peptide: distribution of the trefoil peptides human spasmolytic polypeptide and pS2 in the stomach. Gastroenterology 105: 1110-1116, 1993. [PubMed: 8405856] [Full Text: https://doi.org/10.1016/0016-5085(93)90956-d]
Itoh, H., Tomita, M., Uchino, H., Kobayashi, T., Kataoka, H., Sekiya, R., Nawa, Y. cDNA cloning of rat pS2 peptide and expression of trefoil peptides in acetic acid-induced colitis. Biochem. J. 318: 939-944, 1996. [PubMed: 8836141] [Full Text: https://doi.org/10.1042/bj3180939]
Jakowlew, S. B., Breathnach, R., Jeltsch, J.-M., Masiakowski, P., Chambon, P. Sequence of the pS2 mRNA induced by estrogen in the human breast cancer cell line MCF-7. Nucleic Acids Res. 12: 2861-2878, 1984. [PubMed: 6324130] [Full Text: https://doi.org/10.1093/nar/12.6.2861]
Jeltsch, J. M., Roberts, M., Schatz, C., Garnier, J. M., Brown, A. M. C., Chambon, P. Structure of the human oestrogen-responsive gene pS2. Nucleic Acids Res. 15: 1401-1414, 1987. [PubMed: 3822834] [Full Text: https://doi.org/10.1093/nar/15.4.1401]
Kangaspeska, S., Stride, B., Metivier, R., Polycarpou-Schwarz, M., Ibberson, D., Carmouche, R. P., Benes, V., Gannon, F., Reid, G. Transient cyclical methylation of promoter DNA. Nature 452: 112-115, 2008. [PubMed: 18322535] [Full Text: https://doi.org/10.1038/nature06640]
Lefebvre, O., Chenard, M.-P., Masson, R., Linares, J., Dierich, A., LeMeur, M., Wendling, C., Tomasetto, C., Chambon, P., Rio, M.-C. Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein. Science 274: 259-262, 1996. [PubMed: 8824193] [Full Text: https://doi.org/10.1126/science.274.5285.259]
May, F. E. B., Westley, B. R. Close physical linkage of the genes encoding the pNR-2/pS2 protein and human spasmolytic protein (hSP). Hum. Genet. 99: 303-307, 1997. [PubMed: 9050913] [Full Text: https://doi.org/10.1007/s004390050362]
Metivier, R., Gallais, R., Tiffoche, C., Le Peron, C., Jurkowska, R. Z., Carmouche, R. P., Ibberson, D., Barath, P., Demay, F., Reid, G., Benes, V., Jeltsch, A., Gannon, F., Salbert, G. Cyclical DNA methylation of a transcriptionally active promoter. Nature 452: 45-50, 2008. Note: Erratum: Nature 463: 384 only, 2010. [PubMed: 18322525] [Full Text: https://doi.org/10.1038/nature06544]
Metivier, R., Penot, G., Hubner, M. R., Reid, G., Brand, H., Kos, M., Gannon, F. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115: 751-763, 2003. [PubMed: 14675539] [Full Text: https://doi.org/10.1016/s0092-8674(03)00934-6]
Moisan, J.-P., Mattei, M.-G., Mandel, J.-L. Chromosome localization and polymorphism of an oestrogen-inducible gene specifically expressed in some breast cancers. Hum. Genet. 79: 168-171, 1988. [PubMed: 2899054] [Full Text: https://doi.org/10.1007/BF00280558]
Moisan, J. P., Mattei, M. G., Baeteman-Volkel, M. A., Mattei, J. F., Brown, A. M. C., Garnier, J. M., Jeltsch, J. M., Masiakowsky, P., Roberts, M., Mandel, J. L. A gene expressed in human mammary tumor cells under estrogen control (BCEI) is located in 21q223 and defines an RFLP. (Abstract) Cytogenet. Cell Genet. 40: 701-702, 1985.
Roberts, M., Wallace, J., Jeltsch, J.-M., Berry, M. The 5-prime flanking region of the human pS2 gene mediates its transcriptional activation by estrogen in MCF-7 cells. Biochem. Biophys. Res. Commun. 151: 306-313, 1988. [PubMed: 2450536] [Full Text: https://doi.org/10.1016/0006-291x(88)90594-3]
Seib, T., Blin, N., Hilgert, K., Seifert, M., Theisinger, B., Engel, M., Dooley, S., Zang, K.-D., Welter, C. The three human trefoil genes TFF1, TFF2, and TFF3 are located within a region of 55 kb on chromosome 21q22.3. Genomics 40: 200-202, 1997. [PubMed: 9070946] [Full Text: https://doi.org/10.1006/geno.1996.4511]
Tomasetto, C., Rio, M.-C., Gautier, C., Wolf, C., Hareuveni, M., Chambon, P., Lathe, R. hSP, the domain-duplicated homolog of pS2 protein, is co-expressed with pS2 in stomach but not in breast carcinoma. EMBO J. 9: 407-414, 1990. [PubMed: 2303034] [Full Text: https://doi.org/10.1002/j.1460-2075.1990.tb08125.x]
Watkins, P. C., Tanzi, R. E., Roy, J., Stuart, N., Stanislovitis, P., Gusella, J. F. A cosmid genetic linkage map of chromosome 21 and localization of the breast cancer estrogen-inducible (BCEI) gene. (Abstract) Am. J. Hum. Genet. 41: A189 only, 1987.