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Gene Review

FGF4  -  fibroblast growth factor 4

Homo sapiens

Synonyms: FGF-4, Fibroblast growth factor 4, HBGF-4, HST, HST-1, ...
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Disease relevance of FGF4

  • To determine whether FGFs are overexpressed in human prostate cancers, we analyzed 26 prostate cancer RNAs by reverse transcription-PCR for expression of FGF3, FGF4, and FGF6, which cannot be detected in normal prostate tissue by this technique [1].
  • It is in keeping with the immunohistochemical result that murine teratocarcinoma P19 cells were shown to express FGF8, FGF4, and FGFRI only under undifferentiated growth conditions [2].
  • We previously demonstrated that expression of human FGF4 in the epithelial compartment of murine mammary glands caused hyperplasia during lactation and a dramatic delay in gland involution due to inhibition of cellular apoptosis [3].
  • From this new knowledge, new markers, eg, FGF4, CD30, and OCT-4, of embryonal carcinoma cells are identifying alternative ways of identifying poor risk tumors and leading to renewed interest in study of histopathology of these tumors [4].
  • HST-1 and INT-2 genes which is a member of fibroblast growth factor gene family, are amplified in approximately 50% of primary tumors and all the metastatic tumors of esophageal carcinomas [5].

Psychiatry related information on FGF4

  • Mesenchymal Gremlin expression is lost in limb buds of mouse embryos homozygous for the limb deformity (Id) mutation, which disrupts establishment of the SHH/FGF4 feedback loop [6].
  • This study does not offer direct empirical support for the use of the HST scale as a measurement of the DSM-III-R histrionic personality disorder concept [7].
  • Effects for diagnostic category were found for MMPI Scales 9 (Ma), 0 (Si) and for the HST scale, developed by Morey, Waugh, and Blashfield (1985) for the diagnosis of the histrionic personality disorder [7].

High impact information on FGF4

  • FGF-4 stimulates proliferation of cells in the distal mesenchyme and maintains a signal from the posterior to the distal mesenchyme that appears to be required for elaboration of skeletal elements in the normal proximodistal sequence [8].
  • Expression of the KS3 product as a bacterial fusion protein or in COS cells allowed us to determine that both proteins had significant growth-promoting activity and that the COS cell protein was glycosylated [9].
  • One of the cDNA clones isolated (KS3) corresponded to the 1.2 kb mRNA and transformed NIH 3T3 cell when inserted into a mammalian expression vector [9].
  • Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds [6].
  • One line contained two classes of cells: one with an HST marker chromosome and the other with double minute chromosomes [10].

Chemical compound and disease context of FGF4


Biological context of FGF4

  • To identify potential receptor and heparin binding sites in FGF4, a ternary FGF4-FGFR1-heparin model was constructed by superimposing the FGF4 structure onto FGF2 in the FGF2-FGFR1-heparin structure [16].
  • The most striking effect caused by FGF4 overexpression was on the remodelling of mammary tissue at the end of lactation [17].
  • Transfection of this cell line with the FGF4 gene led to its tumorigenic conversion in a dose-dependent manner as assessed by growth under serum-free conditions, growth in soft agar and growth as xenografts in nude mice [18].
  • Cross-linking experiments done with 125I-FGF2 showed a down-regulation of FGF receptors from the cell surface of FGF4-expressing clones [18].
  • Additionally, FGF4 represses the anterior endoderm markers Hex1 and Nkx2.1 and disrupts foregut morphogenesis [19].

Anatomical context of FGF4

  • The presence of notochord is required for the expression of En1 in neural plate explants in vitro and FGF4 mimics this effect of notochord tissue [20].
  • The mesoderm-inducing effect of FGF2 and FGF4 in Xenopus blastocysts was also enhanced [21].
  • Taken together, these results indicate that the FGF signalling pathway may be involved during tumoral progression of human breast epithelial cells and that there is a dose-dependent relationship between the quantity of FGF4 produced and tumor development [18].
  • At the gastrula stage, exposing endoderm to recombinant FGF4 protein results in an anterior shift in the Pdx1 and CdxB expression domains [19].
  • These expression domains remain sensitive to FGF4 levels throughout early somite stages [19].

Associations of FGF4 with chemical compounds

  • Moreover, we show that FGF4 needs to interact with both the 2-O- and 6-O-sulfates in heparin to exert its optimal biological activity [16].
  • On the other hand, upon HST-1/FGF-4 stimulation, lactate production from Sertoli cells were induced, which is indispensable nutrient for germ cell survival [12].
  • Anaesthesia was maintained for 10 min with vaporizer setting isoflurane 2 vol% and FGF 4 l/min for full-tissue anaesthetic uptake in a semi-closed circle system [22].
  • Three stable transfectants expressing exogenous FGF4 were studied as was a control transfectant only expressing the neomycin resistance gene [14].
  • To clarify the role of RXRbeta and RARgamma in this differentiation program, a modified transient fibroblast growth factor-4 (FGF4) promoter-enhancer reporter assay that reflects effective RA-mediated differentiation of NT2/D1 cells was employed [23].

Physical interactions of FGF4


Regulatory relationships of FGF4

  • The SOX2 gene at 3q27 might be considered an excellent candidate gene for LMS because the corresponding protein stimulates expression of FGF4, an important signaling molecule during limb outgrowth and development [25].
  • Furthermore, overexpressing OCT3 stimulated endogenous FGF-4 expression in MCF7 breast cancer cell line [13].
  • In this study, we show that the promoter of the fibroblast growth factor-4 (FGF-4) gene is strongly activated by B-Myb in HeLa cells and it can serve as a novel diagnostic tool for assessing B-Myb activity [26].

Other interactions of FGF4

  • No expression of FGF3 or FGF4 was detected [1].
  • Amplification of CCND1 alone was found in 9% of the tumours, while EMS1 alone was amplified in 1.6% and FGF4 in 0.8% [27].
  • Clones of FGF4-transfected cells producing different amounts of FGF4 secreted similar quantities of FGF2 [18].
  • At sites where cSef is not normally expressed, FGF4 and FGF2, but not FGF8 beads, induced cSef expression [28].
  • Genomic alterations in PRKCZ, ABL1, and FGF4 were significantly different in patients who died compared with those who survived [29].

Analytical, diagnostic and therapeutic context of FGF4


  1. Increased expression of fibroblast growth factor 6 in human prostatic intraepithelial neoplasia and prostate cancer. Ropiquet, F., Giri, D., Kwabi-Addo, B., Mansukhani, A., Ittmann, M. Cancer Res. (2000) [Pubmed]
  2. Predominant expression of fibroblast growth factor (FGF) 8, FGF4, and FGF receptor 1 in nonseminomatous and highly proliferative components of testicular germ cell tumors. Suzuki, K., Tokue, A., Kamiakito, T., Kuriki, K., Saito, K., Tanaka, A. Virchows Arch. (2001) [Pubmed]
  3. Inhibition of ductal morphogenesis in the mammary gland of WAP -fgf4 transgenic mice. Astigiano, S., Damonte, P., Barbieri, O. Anat. Embryol. (2003) [Pubmed]
  4. Germ cell cancer. Oliver, R.T. Current opinion in oncology. (1999) [Pubmed]
  5. Growth factors in progression of human esophageal and gastric carcinomas. Yoshida, K., Yasui, W., Ito, H., Tahara, E. Experimental pathology. (1990) [Pubmed]
  6. Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Zúñiga, A., Haramis, A.P., McMahon, A.P., Zeller, R. Nature (1999) [Pubmed]
  7. MMPI assessment of the DSM-III-R histrionic personality disorder. Schotte, C., De Doncker, D., Maes, M., Cluydts, R., Cosyns, P. Journal of personality assessment. (1993) [Pubmed]
  8. FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb. Niswander, L., Tickle, C., Vogel, A., Booth, I., Martin, G.R. Cell (1993) [Pubmed]
  9. An oncogene isolated by transfection of Kaposi's sarcoma DNA encodes a growth factor that is a member of the FGF family. Delli Bovi, P., Curatola, A.M., Kern, F.G., Greco, A., Ittmann, M., Basilico, C. Cell (1987) [Pubmed]
  10. Double minute chromosomes and the homogeneously staining regions in chromosomes of a human neuroblastoma cell line. Balaban-Malenbaum, G., Gilbert, F. Science (1977) [Pubmed]
  11. HST-1/FGF-4 gene activation induces spermatogenesis and prevents adriamycin-induced testicular toxicity. Yamamoto, H., Ochiya, T., Tamamushi, S., Toriyama-Baba, H., Takahama, Y., Hirai, K., Sasaki, H., Sakamoto, H., Saito, I., Iwamoto, T., Kakizoe, T., Terada, M. Oncogene (2002) [Pubmed]
  12. HST-1/FGF-4 protects male germ cells from apoptosis under heat-stress condition. Hirai, K., Sasaki, H., Yamamoto, H., Sakamoto, H., Kubota, Y., Kakizoe, T., Terada, M., Ochiya, T. Exp. Cell Res. (2004) [Pubmed]
  13. The POU homeodomain protein OCT3 as a potential transcriptional activator for fibroblast growth factor-4 (FGF-4) in human breast cancer cells. Wang, P., Branch, D.R., Bali, M., Schultz, G.A., Goss, P.E., Jin, T. Biochem. J. (2003) [Pubmed]
  14. FGF4 dissociates anti-tumorigenic from differentiation signals of retinoic acid in human embryonal carcinomas. Maerz, W.J., Baselga, J., Reuter, V.E., Mellado, B., Myers, M.L., Bosl, G.J., Spinella, M.J., Dmitrovsky, E. Oncogene (1998) [Pubmed]
  15. Human HST1 (HSTF1) gene maps to chromosome band 11q13 and coamplifies with the INT2 gene in human cancer. Yoshida, M.C., Wada, M., Satoh, H., Yoshida, T., Sakamoto, H., Miyagawa, K., Yokota, J., Koda, T., Kakinuma, M., Sugimura, T. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  16. Identification of receptor and heparin binding sites in fibroblast growth factor 4 by structure-based mutagenesis. Bellosta, P., Iwahori, A., Plotnikov, A.N., Eliseenkova, A.V., Basilico, C., Mohammadi, M. Mol. Cell. Biol. (2001) [Pubmed]
  17. Hyperplasia and impaired involution in the mammary gland of transgenic mice expressing human FGF4. Morini, M., Astigiano, S., Mora, M., Ricotta, C., Ferrari, N., Mantero, S., Levi, G., Rossini, M., Barbieri, O. Oncogene (2000) [Pubmed]
  18. Tumoral progression of human breast epithelial cells secreting FGF2 and FGF4. Souttou, B., Gamby, C., Crepin, M., Hamelin, R. Int. J. Cancer (1996) [Pubmed]
  19. FGF signaling is necessary for establishing gut tube domains along the anterior-posterior axis in vivo. Dessimoz, J., Opoka, R., Kordich, J.J., Grapin-Botton, A., Wells, J.M. Mech. Dev. (2006) [Pubmed]
  20. Sequential roles for Fgf4, En1 and Fgf8 in specification and regionalisation of the midbrain. Shamim, H., Mahmood, R., Logan, C., Doherty, P., Lumsden, A., Mason, I. Development (1999) [Pubmed]
  21. Role for amplification and expression of glypican-5 in rhabdomyosarcoma. Williamson, D., Selfe, J., Gordon, T., Lu, Y.J., Pritchard-Jones, K., Murai, K., Jones, P., Workman, P., Shipley, J. Cancer Res. (2007) [Pubmed]
  22. Effect of fresh gas flow on isoflurane concentrations during low-flow anaesthesia. Park, J.Y., Kim, J.H., Kim, W.Y., Chang, M.S., Kim, J.Y., Shin, H.W. J. Int. Med. Res. (2005) [Pubmed]
  23. Specific retinoid receptors cooperate to signal growth suppression and maturation of human embryonal carcinoma cells. Spinella, M.J., Kitareewan, S., Mellado, B., Sekula, D., Khoo, K.S., Dmitrovsky, E. Oncogene (1998) [Pubmed]
  24. Regulation of the FGF-4 gene by a complex distal enhancer that functions in part as an enhanceosome. Luster, T.A., Rizzino, A. Gene (2003) [Pubmed]
  25. Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other Hand/Foot anomalies maps to human chromosome 3q27. van Bokhoven, H., Jung, M., Smits, A.P., van Beersum, S., Rüschendorf, F., van Steensel, M., Veenstra, M., Tuerlings, J.H., Mariman, E.C., Brunner, H.G., Wienker, T.F., Reis, A., Ropers, H.H., Hamel, B.C. Am. J. Hum. Genet. (1999) [Pubmed]
  26. Effects of B-Myb on gene transcription: phosphorylation-dependent activity ans acetylation by p300. Johnson, L.R., Johnson, T.K., Desler, M., Luster, T.A., Nowling, T., Lewis, R.E., Rizzino, A. J. Biol. Chem. (2002) [Pubmed]
  27. High-throughput tissue microarray analysis of 11q13 gene amplification (CCND1, FGF3, FGF4, EMS1) in urinary bladder cancer. Zaharieva, B.M., Simon, R., Diener, P.A., Ackermann, D., Maurer, R., Alund, G., Knönagel, H., Rist, M., Wilber, K., Hering, F., Schönenberger, A., Flury, R., Jäger, P., Fehr, J.L., Mihatsch, M.J., Gasser, T., Sauter, G., Toncheva, D.I. J. Pathol. (2003) [Pubmed]
  28. Sef is synexpressed with FGFs during chick embryogenesis and its expression is differentially regulated by FGFs in the developing limb. Harduf, H., Halperin, E., Reshef, R., Ron, D. Dev. Dyn. (2005) [Pubmed]
  29. Array-comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas. Liu, C.J., Lin, S.C., Chen, Y.J., Chang, K.M., Chang, K.W. Mol. Carcinog. (2006) [Pubmed]
  30. Fusion and amplification of two originally non-syntenic chromosomal regions in a mammary carcinoma cell line. Lafage, M., Pedeutour, F., Marchetto, S., Simonetti, J., Prosperi, M.T., Gaudray, P., Birnbaum, D. Genes Chromosomes Cancer (1992) [Pubmed]
  31. Human RPE cells express the FGFR2IIIc and FGFR3IIIc splice variants and FGF9 as a potential high affinity ligand. Alizadeh, M., Miyamura, N., Handa, J.T., Hjelmeland, L.M. Exp. Eye Res. (2003) [Pubmed]
  32. Vascular endothelial growth factor, epidermal growth factor and fibroblast growth factor-4 and -10 stimulate trophoblast plasminogen activator system and metalloproteinase-9. Anteby, E.Y., Greenfield, C., Natanson-Yaron, S., Goldman-Wohl, D., Hamani, Y., Khudyak, V., Ariel, I., Yagel, S. Mol. Hum. Reprod. (2004) [Pubmed]
  33. Association of INT2/HST1 coamplification in primary breast cancer with hormone-dependent phenotype and poor prognosis. Borg, A., Sigurdsson, H., Clark, G.M., Fernö, M., Fuqua, S.A., Olsson, H., Killander, D., McGurie, W.L. Br. J. Cancer (1991) [Pubmed]
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