Alternative titles; symbols
HGNC Approved Gene Symbol: TFF3
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38) : 21:42,311,667-42,315,409 (from NCBI)
The trefoil factor family (TFF) includes the protease-resistant peptides TFF1 (113710), TFF2 (182590), and TFF3. All TFF peptides contain a characteristic domain in which 6 cysteines in a peptide chain of 38 or 39 amino acids form 3 disulfide bonds to create a characteristic 3-leaved structure that gives the family its name (Thim, 1989). TFF peptides interact with mucins and have an influence on mucus viscosity. They also promote migration of epithelial cells, are linked to antiapoptosis, induce cell scattering, trigger chemotaxis, and participate in immune responses (Paulsen et al., 2008).
Podolsky et al. (1993) reported that ITF was expressed in the epithelial mucosal layer of the small intestine and colon. Thim et al. (1995) produced ITF from human and rat in Saccharomyces cerevisiae. cDNAs encoding human and rat ITF were cloned by PCR from a human normal colon library and a rat small intestinal epithelial cell library, respectively. The human ITF monomer showed that 6 of the 7 cysteines were disulfide-linked, forming 3 disulfide bridges.
Probst et al. (1996) identified the ITF peptide in human brain and pituitary. With RT-PCR, they isolated and cloned the transcript from human hypothalamus. By immunohistochemical means, neurons expressing ITF were identified in 2 magnocellular hypothalamic nuclei, the paraventricular and periventricular nuclei. Human ITF polypeptide was also observed in Herring bodies of the neurohypophysis and in secretory cells of the adenohypophysis. Probst et al. (1996) stated that this localization may suggest a modulatory action on the classic magnocellular nonapeptides vasopressin (192340) and oxytocin (167050).
Itoh et al. (1996) examined the expression of rat Itf, rat pS2 (TFF1), and rat Sp (TFF2) during the course of acetic acid-induced colitis. Itf was downregulated during the acute phase of colitis and then upregulated during recovery.
Taupin et al. (1999) found that Itf-deficient mice, in which colonic restitution is lethally impaired, showed reduced expression of the gastric trefoil genes Sp and pS2, suggesting that trefoil peptides may individually regulate transcription of the entire family. In gastric cell lines, the trefoils were shown to act in a manner suggestive of immediate-early genes capable of auto- and cross-induction through cis-acting regulatory regions.
Using microarray analysis, Bignotti et al. (2008) found that TFF3 was the most highly upregulated gene in 19 poorly differentiated endometrioid endometrial carcinomas (G3-EECs) compared with normal endometrium biopsies. Quantitative real-time PCR confirmed TFF3 upregulation in G3-EECs. Immunocytochemical analysis detected TFF3 protein in the cytoplasm of 79% of G3-EECs compared with only 18% of controls. Patients harboring G3-EECs had significantly higher TFF3 serum concentrations by ELISA than healthy patients or patients harboring endometrial hyperplasia.
Chinery et al. (1996) showed that the TFF3 gene segregated with chromosome 21q in a rodent/human somatic cell hybrid panel. By FISH, they mapped the TFF3 gene to chromosome 21q22.3. Triple FISH, together with physical mapping of human genomic DNA using pulsed field gel electrophoresis, revealed tight linkage between the TFF3 gene and the TFF1 and TFF2 genes. Using PCR analysis of a somatic cell hybrid panel and FISH using 2 large genomic recombinants cloned in a bacterial artificial chromosome, Schmitt et al. (1996) confirmed the mapping of the TFF3 gene to chromosome 21q22.3. Seib et al. (1997) found that the TFF1, TFF2, and TFF3 genes are clustered within a 55-kb region.
Burmeister and Meyer (1997) demonstrated that the mouse Tff3 gene maps to chromosome 17.
Mashimo et al. (1996) produced mice unable to express Itf by means of targeted disruption of the Itf gene through homologous recombination. Itf -/- mice lacked Itf protein in colon and small intestine, and expression of the other trefoil proteins, Tff1 and Tff2, was normal. Itf -/- mice developed normally. Mashimo et al. (1996) reported that although the Itf -/- mice exhibited normal mucosal architecture, their proliferative intestinal compartments were expanded and there was impaired migration of epithelium to the mucosal surface. The mice were markedly sensitive to the effects of ingested dextran sulfate sodium (DSS), and DSS treatment resulted in the presence of multiple sites of ulceration and hemorrhage in colon. Histologic examination revealed large stretches of denuded epithelium, and there was no evidence of reepithelialization. Colons of most DSS-treated wildtype mice were unaffected. Wildtype mice did display microscopic evidence of mucosal erosion, but most of the erosions were small and exhibited features of mucosal healing. Mashimo et al. (1996) demonstrated that repletion of Itf -/- mice by luminal instillation of recombinant Itf peptide resulted in healing. Mashimo et al. (1996) concluded that ITF has a central role in the maintenance and repair of intestinal mucosa. They noted that trefoil factors are unusual in their resistance to acid and proteolytic enzymes, and that they therefore have potential as orally administered therapy for various forms of gastrointestinal injury, including inflammatory bowel disease.
Paulsen et al. (2008) found that Tff3 was not expressed in normal mouse corneal epithelium, but that its expression was upregulated after epithelial injury in 2 models of corneal wound healing. Reepithelialization of corneal wounds was significantly prolonged in Tff3 -/- mice compared with wildtype mice. Exogenous application of recombinant Tff3 to alkali-induced corneal wounds accelerated wound healing in both Tff3 -/- and wildtype corneas.
Bignotti, E., Ravaggi, A., Tassi, R. A., Calza, S., Rossi, E., Falchetti, M., Romani, C., Bandiera, E., Odicino, F. E., Pecorelli, S., Santin, A. D. Trefoil factor 3: a novel serum marker identified by gene expression profiling in high-grade endometrial carcinomas. Brit. J. Cancer 99: 768-773, 2008. [PubMed: 18682706] [Full Text: https://doi.org/10.1038/sj.bjc.6604546]
Burmeister, M., Meyer, G. E. The trefoil gene maps to mouse chromosome 17. Mammalian Genome 8: 223-224, 1997. [PubMed: 9072957] [Full Text: https://doi.org/10.1007/s003359900637]
Chinery, R., Williamson, J., Poulsom, R. The gene encoding human intestinal trefoil factor (TFF3) is located on chromosome 21q22.3 clustered with other members of the trefoil peptide family. Genomics 32: 281-284, 1996. [PubMed: 8833157] [Full Text: https://doi.org/10.1006/geno.1996.0117]
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]
Mashimo , H., Wu, D.-C., Podolsky, D. K., Fishman, M. C. Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science 274: 262-265, 1996. [PubMed: 8824194] [Full Text: https://doi.org/10.1126/science.274.5285.262]
Paulsen, F. P., Woon, C.-W., Varoga, D., Jansen, A., Garreis, F., Jager, K., Amm, M., Podolsky, D. K., Steven, P., Barker, N. P., Sel, S. Intestinal trefoil factor/TFF3 promotes re-epithelialization of corneal wounds. J. Biol. Chem. 283: 13418-13427, 2008. [PubMed: 18326859] [Full Text: https://doi.org/10.1074/jbc.M800177200]
Podolsky, D. K., Lynch-Devaney, K., Stow, J. L., Oates, P., Murgue, B., DeBeaumont, M., Sands, B. E., Mahida, Y. R. Identification of human intestinal trefoil factor: goblet cell-specific expression of a peptide targeted for apical secretion. J. Biol. Chem. 268: 6694-6702, 1993. Note: Erratum: J. Biol. Chem. 268: 12230 only, 1993. [PubMed: 8454642]
Probst, J. C., Zetzsche, T., Weber, M., Theilemann, P., Skutella, T., Landgraf, R., Jirikowski, G. F. Human intestinal trefoil factor is expressed in human hypothalamus and pituitary: evidence for a novel neuropeptide. FASEB J. 10: 1518-1523, 1996. [PubMed: 8940297] [Full Text: https://doi.org/10.1096/fasebj.10.13.8940297]
Schmitt, H., Wundrack, I., Beck, S., Gott, P., Welter, C., Shizuya, H., Simon, M. I., Blin, N. A third P-domain peptide gene (TFF3), human intestinal trefoil factor, maps to 21q22.3. Cytogenet. Cell Genet. 72: 299-302, 1996. [PubMed: 8641134] [Full Text: https://doi.org/10.1159/000134208]
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]
Taupin, D., Wu, D.-C., Jeon, W.-K., Devaney, K., Wang, T. C., Podolsky, D. K. The trefoil gene family are coordinately expressed immediate-early genes: EGF receptor- and MAP kinase-dependent interregulation. J. Clin. Invest. 103: R31-R38, 1999. [PubMed: 10225980] [Full Text: https://doi.org/10.1172/JCI3304]
Thim, L., Woldike, H. F., Nielsen, P. F., Christensen, M., Lynch-Devaney, K., Podolsky, D. K. Characterization of human and rat intestinal trefoil factor produced in yeast. Biochemistry 34: 4757-4764, 1995. [PubMed: 7718582] [Full Text: https://doi.org/10.1021/bi00014a033]
Thim, L. A new family of growth factor-like peptides: 'trefoil' disulphide loop structures as a common feature in breast cancer associated peptide (pS2), pancreatic spasmolytic polypeptide (PSP), and frog skin peptides (spasmolysins). FEBS Lett. 250: 85-90, 1989. [PubMed: 2737304] [Full Text: https://doi.org/10.1016/0014-5793(89)80690-8]