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Gene Review

TFF2  -  trefoil factor 2

Homo sapiens

Synonyms: SML1, SP, Spasmolysin, Spasmolytic polypeptide, Trefoil factor 2
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Disease relevance of TFF2

  • RESULTS: UACL glands containing TFF1 and TFF2 were observed in six patients with pouchitis [1].
  • There was a significant correlation between TFF1 and TFF2 expression in gastric cancer and adjacent non-cancer tissues (p<0.001) [2].
  • TFF2 expression was demonstrated in 87.5% of non-cancer patients, 34% of gastric carcinomas, and 58% of adjacent non-cancer tissues [2].
  • In addition, a significantly higher prevalence of positive TFF2 staining was detected in large, diffuse tumors and in tumors with lymph node metastasis [3].
  • RESULTS: Immunohistochemical tests for MUC2 and TFF2 were negative both in samples of Barret's metaplasia and in SCC [4].

Psychiatry related information on TFF2


High impact information on TFF2

  • Counterparts of skin tachykinins in mammalian tissues are SP, neurokinin A, and neurokinin B [10].
  • Substance P (SP), first identified by bioassay as early as 1931 but sequenced only in 1971, several years after the elucidation of the structure of eledoisin from molluscan tissues and of physalaemin from amphibian skin, may be considered as a prototype of the tachykinins [10].
  • Substance P (SP), a neurotachykinin, is important in a number of inflammatory processes in which the endothelial cell also plays a critical role [11].
  • Autoradiographic ligand binding to human umbilical cord sections demonstrates the presence of SP binding sites with characteristics of the neurokinin 1 (NK-1) receptor (displacement by GTP analogues and the NK-1 specific antagonist CP-96,345) on human umbilical arterial, but not venous, endothelium [11].
  • In culture, human umbilical venous endothelial cells (HUVECs) and human aortic endothelial cells express low levels of available SP binding sites [11].

Chemical compound and disease context of TFF2


Biological context of TFF2


Anatomical context of TFF2


Associations of TFF2 with chemical compounds


Physical interactions of TFF2

  • In contrast, pronounced binding differences were observed in cells with a strong preference for USF to interact specifically with the TFF2 E box, while Myc was not above background [17].
  • Substance P (SP) participates in acute intestinal inflammation via binding to the G-protein-coupled neurokinin-1 receptor (NK-1R) and release of proinflammatory cytokines from colonic epithelial cells [26].

Enzymatic interactions of TFF2


Regulatory relationships of TFF2

  • TFF2 is co-expressed with TFF1 in gastric surface epithelial cells, but its potential role in vivo is unclear [25].
  • TFF1 and TFF3 were mainly expressed in goblet cells and TFF2 in columnar cells in all the types of intestinal metaplasia [28].
  • RESULTS: It was observed that the TFF2 promoter is specifically and efficiently activated by USF transcription factors but not by c-Myc [17].
  • SP also stimulated IL-3-dependent colony formation of whole bone marrow MNCs in a soft agar culture system, but showed no such activity on isolated CD34+ cells in this system [29].
  • Furthermore, SP can induce IL-1 type I receptor in stroma [30].

Other interactions of TFF2

  • TFF3 mRNA localized patchily throughout the UACL, whereas TFF1 mRNA was found in the upper portions of the lineage and TFF2 mRNA and its product in the acini [31].
  • TFF1, TFF2, and MUC6 were found in 84%, 92%, and 65% of GMD, respectively [32].
  • MUC5AC and TFF2 were expressed at similar high levels in each clinical group [33].
  • In small bile ducts, TFF2/DMBT1 is induced in damaged ducts irrespective of etiologies [34].
  • Using specific inhibitors, the signaling cascades responsible for the motogenic response were shown to differ drastically when EGF was compared with TFF2 [35].

Analytical, diagnostic and therapeutic context of TFF2


  1. Ulcer associated cell lineage glands expressing trefoil peptide genes are induced by chronic ulceration in ileal pouch mucosa. Pera, M., Heppell, J., Poulsom, R., Teixeira, F.V., Williams, J. Gut (2001) [Pubmed]
  2. Expression of trefoil peptides (TFF1, TFF2, and TFF3) in gastric carcinomas, intestinal metaplasia, and non-neoplastic gastric tissues. Leung, W.K., Yu, J., Chan, F.K., To, K.F., Chan, M.W., Ebert, M.P., Ng, E.K., Chung, S.C., Malfertheiner, P., Sung, J.J. J. Pathol. (2002) [Pubmed]
  3. Expression of trefoil factor family members correlates with patient prognosis and neoangiogenesis. Dhar, D.K., Wang, T.C., Tabara, H., Tonomoto, Y., Maruyama, R., Tachibana, M., Kubota, H., Nagasue, N. Clin. Cancer Res. (2005) [Pubmed]
  4. Differential expression of mucins and trefoil peptides in native epithelium, Barrett's metaplasia and squamous cell carcinoma of the oesophagus. Labouvie, C., Machado, J.C., Carneiro, F., Sarbia, M., Vieth, M., Porschen, R., Seitz, G., Blin, N. J. Cancer Res. Clin. Oncol. (1999) [Pubmed]
  5. The diurnal rhythm of the cytoprotective human trefoil protein TFF2 is reduced by factors associated with gastric mucosal damage: ageing, Helicobacter pylori infection, and sleep deprivation. Johns, C.E., Newton, J.L., Westley, B.R., May, F.E. Am. J. Gastroenterol. (2005) [Pubmed]
  6. Valproic acid inhibits substance P-induced activation of protein kinase C epsilon and expression of the substance P receptor. Lieb, K., Treffurth, Y., Hamke, M., Akundi, R.S., von Kleinsorgen, M., Fiebich, B.L. J. Neurochem. (2003) [Pubmed]
  7. Facilitation of memory by peripheral administration of substance P and naloxone using avoidance and habituation learning tasks. Tomaz, C., Aguiar, M.S., Nogueira, P.J. Neuroscience and biobehavioral reviews. (1990) [Pubmed]
  8. Positively reinforcing effects of the neurokinin substance P in the basal forebrain: mediation by its C-terminal sequence. Hasenöhrl, R.U., Gerhardt, P., Huston, J.P. Exp. Neurol. (1992) [Pubmed]
  9. Substance P and neurokinin-1 receptor modulation of HIV. Ho, W.Z., Douglas, S.D. J. Neuroimmunol. (2004) [Pubmed]
  10. The tachykinin peptide family. Severini, C., Improta, G., Falconieri-Erspamer, G., Salvadori, S., Erspamer, V. Pharmacol. Rev. (2002) [Pubmed]
  11. Functional neurokinin 1 receptors for substance P are expressed by human vascular endothelium. Greeno, E.W., Mantyh, P., Vercellotti, G.M., Moldow, C.F. J. Exp. Med. (1993) [Pubmed]
  12. The gene encoding the human spasmolytic protein (SML1/hSP) is in 21q 22.3, physically linked to the homologous breast cancer marker gene BCEI/pS2. Tomasetto, C., Rockel, N., Mattei, M.G., Fujita, R., Rio, M.C. Genomics (1992) [Pubmed]
  13. Allergen induced tff2 is expressed by mucus-producing airway epithelial cells but is not a major regulator of inflammatory responses in the murine lung. Nikolaidis, N.M., Wang, T.C., Hogan, S.P., Rothenberg, M.E. Exp. Lung Res. (2006) [Pubmed]
  14. Differential chemotactic activities of sensory neuropeptides for human peripheral blood mononuclear cells. Schratzberger, P., Reinisch, N., Prodinger, W.M., Kähler, C.M., Sitte, B.A., Bellmann, R., Fischer-Colbrie, R., Winkler, H., Wiedermann, C.J. J. Immunol. (1997) [Pubmed]
  15. Recent advances in neurokinin receptor antagonists. Gao, Z., Peet, N.P. Current medicinal chemistry. (1999) [Pubmed]
  16. Substance P and histamine induce interleukin-6 expression in human astrocytoma cells by a mechanism involving protein kinase C and nuclear factor-IL-6. Lieb, K., Schaller, H., Bauer, J., Berger, M., Schulze-Osthoff, K., Fiebich, B.L. J. Neurochem. (1998) [Pubmed]
  17. Gastroprotective peptide trefoil factor family 2 gene is activated by upstream stimulating factor but not by c-Myc in gastrointestinal cancer cells. Al-azzeh, E., Dittrich, O., Vervoorts, J., Blin, N., Gött, P., Lüscher, B. Gut (2002) [Pubmed]
  18. Trefoil factor family-peptides promote migration of human bronchial epithelial cells: synergistic effect with epidermal growth factor. Oertel, M., Graness, A., Thim, L., Bühling, F., Kalbacher, H., Hoffmann, W. Am. J. Respir. Cell Mol. Biol. (2001) [Pubmed]
  19. Development and evaluation of an ELISA for human trefoil factor 3. Vestergaard, E.M., Poulsen, S.S., Grønbaek, H., Larsen, R., Nielsen, A.M., Ejskjaer, K., Clausen, J.T., Thim, L., Nexø, E. Clin. Chem. (2002) [Pubmed]
  20. Trefoil factors are expressed in human and rat endocrine pancreas: differential regulation by growth hormone. Jackerott, M., Lee, Y.C., M??llg??rd, K., Kofod, H., Jensen, J., Rohleder, S., Neubauer, N., Gaarn, L.W., Lykke, J., Dodge, R., Dalgaard, L.T., S??strup, B., Jensen, D.B., Thim, L., Nex??, E., Thams, P., Bisgaard, H.C., Nielsen, J.H. Endocrinology (2006) [Pubmed]
  21. Secretory peptides TFF1 and TFF3 synthesized in human conjunctival goblet cells. Langer, G., Jagla, W., Behrens-Baumann, W., Walter, S., Hoffmann, W. Invest. Ophthalmol. Vis. Sci. (1999) [Pubmed]
  22. TFF peptides in the human efferent tear ducts. Paulsen, F.P., Hinz, M., Schaudig, U., Thale, A.B., Hoffmann, W. Invest. Ophthalmol. Vis. Sci. (2002) [Pubmed]
  23. Indometacin up-regulates TFF2 expression in gastric epithelial cells. Koitabashi, A., Shimada, T., Fujii, Y., Hashimoto, T., Hosaka, K., Tabei, K., Namatame, T., Yoneda, M., Hiraishi, H., Terano, A. Aliment. Pharmacol. Ther. (2004) [Pubmed]
  24. Up-regulation of TFF expression by PPARgamma ligands in gastric epithelial cells. Shimada, T., Koitabashi, A., Kuniyoshi, T., Hashimoto, T., Yoshiura, K., Yoneda, M., Hiraishi, H., Terano, A. Aliment. Pharmacol. Ther. (2003) [Pubmed]
  25. Trefoil factor-2, human spasmolytic polypeptide, promotes branching morphogenesis in MCF-7 cells. Lalani, E.N., Williams, R., Jayaram, Y., Gilbert, C., Chaudhary, K.S., Siu, L.S., Koumarianou, A., Playford, R., Stamp, G.W. Lab. Invest. (1999) [Pubmed]
  26. Metalloproteinases and transforming growth factor-alpha mediate substance P-induced mitogen-activated protein kinase activation and proliferation in human colonocytes. Koon, H.W., Zhao, D., Na, X., Moyer, M.P., Pothoulakis, C. J. Biol. Chem. (2004) [Pubmed]
  27. Receptors mediating the effects of substance P and neurokinin A on mucus secretion and smooth muscle tone of the ferret trachea: potentiation by an enkephalinase inhibitor. Webber, S.E. Br. J. Pharmacol. (1989) [Pubmed]
  28. Expression of trefoil peptides in the subtypes of intestinal metaplasia. Kim, B.W., Kim, K.M., Lee, B.I., Maeng, L.S., Choi, H., Cho, S.H., Chae, H.S., Kim, J.K., Choi, K.Y., Chung, I.S. Peptides (2004) [Pubmed]
  29. Stimulatory effects of substance P on CD34 positive cell proliferation and differentiation in vitro are mediated by the modulation of stromal cell function. Hiramoto, M., Aizawa, S., Iwase, O., Nakano, M., Toyama, K., Hoque, M., Nabeshima, R., Kaidow, A., Imai, T., Hoshi, H., Handa, H. Int. J. Mol. Med. (1998) [Pubmed]
  30. Hematopoietic modulation by the tachykinins. Rameshwar, P., Gascón, P. Acta Haematol. (1997) [Pubmed]
  31. Duodenal content reflux esophagitis in the rat: an animal model for the ulcer-associated cell lineage (UACL)? Hanby, A.M., Pera, M., Filipe, I., Duranceau, A., Wright, N.A., Pera, M., Grande, L., Poulsom, R. Am. J. Pathol. (1997) [Pubmed]
  32. Metaplasia of the duodenum shows a Helicobacter pylori-correlated differentiation into gastric-type protein expression. Van De Bovenkamp, J.H., Korteland-Van Male, A.M., Büller, H.A., Einerhand, A.W., Dekker, J. Hum. Pathol. (2003) [Pubmed]
  33. Barrett's esophagus is characterized by expression of gastric-type mucins (MUC5AC, MUC6) and TFF peptides (TFF1 and TFF2), but the risk of carcinoma development may be indicated by the intestinal-type mucin, MUC2. Warson, C., Van De Bovenkamp, J.H., Korteland-Van Male, A.M., Büller, H.A., Einerhand, A.W., Ectors, N.L., Dekker, J. Hum. Pathol. (2002) [Pubmed]
  34. Site-characteristic expression and induction of trefoil factor family 1, 2 and 3 and malignant brain tumor-1 in normal and diseased intrahepatic bile ducts relates to biliary pathophysiology. Sasaki, M., Tsuneyama, K., Saito, T., Kataoka, H., Mollenhauer, J., Poustka, A., Nakanuma, Y. Liver Int. (2004) [Pubmed]
  35. Epidermal growth factor and trefoil factor family 2 synergistically trigger chemotaxis on BEAS-2B cells via different signaling cascades. Chwieralski, C.E., Schnurra, I., Thim, L., Hoffmann, W. Am. J. Respir. Cell Mol. Biol. (2004) [Pubmed]
  36. Patterns of expression of trefoil peptides and mucins in gastric polyps with and without malignant transformation. Nogueira, A.M., Machado, J.C., Carneiro, F., Reis, C.A., Gött, P., Sobrinho-Simões, M. J. Pathol. (1999) [Pubmed]
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