Disease relevance of Fgf7

• KGF is currently being evaluated in clinical trials to test its ability to ameliorate severe oral mucositis (OM) that results from cancer chemoradiotherapy [1].
• In a phase 3 trial involving patients who were treated with myeloablative chemoradiotherapy before autologous peripheral blood progenitor cell transplantation for hematologic malignancies, KGF significantly reduced both the incidence and duration of severe OM [1].
• These results suggest that KGF may be of clinical value in reducing radiation toxicity to the intestine [2].
• Thus KGF can act as a potent proliferative inducer in mammary and specific urogenital tissue and can contribute to the development of adenocarcinoma of the mammary gland in a manner strongly reminiscent of receptor-related ligand, int-2 [3].
• Keratinocyte growth factor induces mammary and prostatic hyperplasia and mammary adenocarcinoma in transgenic mice [3].

Psychiatry related information on Fgf7

• KGF expression was also detected in tissues isolated from human embryos, suggesting similar functions for KGF in human development [4].

High impact information on Fgf7

• It is shown here that activated gamma delta T cells obtained from skin and intestine express the epithelial cell mitogen keratinocyte growth factor (KGF) [5].
• In contrast, intraepithelial alpha beta T cells, as well as all lymphoid alpha beta and gamma delta T cell populations tested, did not produce KGF or promote the growth of cultured epithelial cells [5].
• The pattern of binding competition by related fibroblast growth factors (FGFs) indicated that this receptor had high affinity for acidic FGF as well as KGF [6].
• Among several transformed foci identified, one demonstrated the acquisition of specific high-affinity KGF binding sites [6].
• The KGF transcript was present in stromal cells derived from epithelial tissues [7].

Chemical compound and disease context of Fgf7

• To understand the relevance of intraepithelial lymphocyte (IEL)-derived KGF expression on epithelial growth, we used a mouse model of villus atrophy by the administration of total parenteral nutrition, and a model of villus hypertrophy by the creation of a short bowel syndrome [8].
• Induction of FGF-7 expression by doxycycline in the Ccsp-rtta x (Teto)(7)-cmv-fgf-7 mice caused marked epithelial cell proliferation, adenomatous hyperplasia, and pulmonary infiltration with mononuclear cells [9].
• The in vitro findings are clinically relevant because KGF protected keratinocytes in organ-cultured human scalp hair follicles from the toxicity of the xenobiotic menadione [10].
• However, KGF-treated recipients receiving TBI or Cy/TBI BMS were not GVHD-free, as shown by lower body weights compared with BM groups [11].
• These results demonstrate that KGF induces hypertriglyceridemia by increasing hepatic triglyceride secretion, with the fatty acids provided by lipolysis making a major contribution [12].

Biological context of Fgf7

• Keratinocyte growth factor is required for hair development but not for wound healing [13].
• Over time, their fur developed a matted appearance, very similar to that of the rough mouse, whose recessive mutation maps at or near the KGF locus on mouse chromosome 2 [13].
• The upregulation of KGF after epithelial injury suggested it had an important role in tissue repair [1].
• These results demonstrate that the peptide binds directly and specifically to KGF and argue that this region of the receptor constitutes part or all of the KGF binding site [14].
• KGF also stimulated the rapid tyrosine phosphorylation of a 90-kDa protein in Balb/MK cells but not in NIH/3T3 fibroblasts [15].

Anatomical context of Fgf7

• Fgf7 and Fgf10, the main ligands for FgfR2-IIIb, are expressed in the mesenchyme surrounding the thymic epithelial primordium, and Fgf10-deficient mice also exhibit impaired thymic growth [16].
• Among these FGF genes, only Fgf7 was found to be expressed in the hair follicle [17].
• To explore KGF's function in vivo, we used embryonic stem cell technology to generate mice lacking KGF [13].
• Targeting expression of keratinocyte growth factor to keratinocytes elicits striking changes in epithelial differentiation in transgenic mice [18].
• Large induction of keratinocyte growth factor expression in the dermis during wound healing [19].

Associations of Fgf7 with chemical compounds

• Mutant proteins, produced in bacteria, were tested for their ability to bind heparin, bind and activate the KGF receptor, and induce DNA synthesis [20].
• However, deletion of 29 residues resulted in significantly reduced ability to stimulate KGF receptor tyrosine-kinase activity and DNA synthesis, although this mutant bound the receptor at high affinity [20].
• Heparan sulfate proteoglycan modulates keratinocyte growth factor signaling through interaction with both ligand and receptor [21].
• Pretreatment of tumor cells with suramin or neutralizing antibodies to bFGF or keratinocyte growth factor (KGF) circumvented resistance in one of the tumor lines, confirming autocrine-mediated resistance [22].
• In addition, KGF is apparently interacting with an as yet unidentified type of low affinity binding site that is not affected by chlorate or heparan sulfate-degrading enzymes [23].

Physical interactions of Fgf7

• In the urinary bladder, FGF-7 is transported from the lamina propria across the urothelial basement membrane to where it ultimately binds to splice variants of the FGFR2 receptor present on the basolateral surface of transitional epithelial cells [24].
• Heparin restored the high affinity binding of aFGF to chlorate-treated cells and completely abolished the high affinity binding of KGF [23].
• Taken together our data suggest that, in vivo, Kgf may interact with androgen receptor signalling but it is not a direct target of androgen action [25].

Regulatory relationships of Fgf7

• Ribosomal S6 kinase as a mediator of keratinocyte growth factor-induced activation of Akt in epithelial cells [26].
• KGF stimulated 3H-thymidine incorporation in these end buds in the absence and presence of epidermal growth factor [27].
• Furthermore, the administration of anti-KGF neutralizing antibody significantly inhibited acceleration of HF morphogenesis in p75NTR knockout mice in vivo [28].
• FGF-10 is also expressed at about a 15-fold higher molar level than KGF [29].
• Keratinocyte growth factor decreases total parenteral nutrition-induced apoptosis in mouse intestinal epithelium via Bcl-2 [30].

Other interactions of Fgf7

• No difference could be observed between transgenic and control lungs in either the level or distribution of Bmp4, Wnt2 and Fgf7 RNA [31].
• Characterization of the receptor for keratinocyte growth factor. Evidence for multiple fibroblast growth factor receptors [15].
• Altogether, our results suggest that the amino-terminal part of KGF and bFGF plays an important role in determining their receptor binding specificity [32].
• High affinity binding of KGF was acquired only when also domain 2 in this chimera was replaced by its homologous domain from FGFR2 [33].
• To further evaluate the roles of FGFs in tooth development, we analyzed the roles of FGF-3, FGF-7, and FGF-10 in developing mouse teeth [34].

Analytical, diagnostic and therapeutic context of Fgf7

• Preclinical data from several animal models demonstrated that recombinant human KGF could enhance the regenerative capacity of epithelial tissues and protect them from a variety of toxic exposures [1].
• In situ hybridization studies revealed highest levels of KGF mRNA expression in the dermis at the wound edge and in the hypodermis below the wound [19].
• Furthermore, after approximately 24 h, KGF as well as TGF alpha induced EGFR down-regulation based on Western blot analysis and 125I-EGF binding [35].
• Treatment with both KGF and stem cell factor (previously shown to enhance intestinal crypt survival after total-body irradiation) increased the number of surviving crypt cells after irradiation to levels similar to that in animals treated with KGF alone [2].
• Moreover, functional assays in organ culture and in vivo and analysis of agents regulating KGF expression reinforced the idea that KGF acts predominantly on epithelial cells [36].

References