Fibroblast growth factors, their receptors and signaling.
TL;DR: FGF signaling also appears to play a role in tumor growth and angiogenesis, and autocrine FGF signaling may be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state.
Abstract: Fibroblast growth factors (FGFs) are small polypeptide growth factors, all of whom share in common certain structural characteristics, and most of whom bind heparin avidly. Many FGFs contain signal peptides for secretion and are secreted into the extracellular environment, where theycan bind to the heparan-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM). From this reservoir, FGFs mayact directlyon target cells, or theycan be released through digestion of the ECM or the activityof a carrier protein, a secreted FGF binding protein. FGFs bind specific receptor tyrosine kinases in the context of HLGAGs and this binding induces receptor dimerization and activation, ultimatelyresulting in the activation of various signal transduction cascades. Some FGFs are potent angiogenic factors and most playimportant roles in embry onic development and wound healing. FGF signaling also appears to playa role in tumor growth and angiogenesis, and autocrine FGF signaling maybe particularlyimportant in the progression of steroid hormone-dependent cancers to a hormone-independent state.
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TL;DR: There are numerous studies in the literature reporting the application of phage display technology for the development of peptides and proteins capable of functioning as FGF mimetics or traps, which are able to modulate FGF-related signaling pathways.
3 citations
Dissertation•
01 May 2018
TL;DR: It is shown that MIER1α localizes in the nucleus in breast carcinoma MCF7 cells without an intrinsic nuclear localization signal (NLS), and details of the mechanism responsible for MIer1α nucleocytoplasmic shuttling in a breast cancer carcinoma cell line are provided.
Abstract: Temporal and spatial regulation of the subcellular distribution of transcriptional regulators is important to ensure their proper functioning in a cell. Mesoderm induction early response 1 α (MIER1α) has been implicated as a tumour suppressor in breast cancer. Analysis of MIER1α subcellular localization in breast samples revealed a stepwise translocation from the nucleus to the cytoplasm during progression to invasive carcinoma (McCarthy et al., 2008). Therefore, an investigation of MIER1α nucleocytoplasmic shuttling is critical to unraveling its role in breast cancer progression.
Structurally, MIER1α has conserved domains found in a number of other transcriptional regulators, including N-terminal acidic stretches, ELM2 and SANT domains. However, none of these domains contain the predicted nuclear import or export signals. In this thesis, I show that MIER1α localizes in the nucleus in breast carcinoma MCF7 cells without an intrinsic nuclear localization signal (NLS). Although MIER1α has been shown to bind to ERα, active nuclear import of MIER1α is not through interaction with ERα; instead, it depends on interaction and co-transport with HDAC1/2 through a “piggyback” mechanism. Deletion analysis demonstrated that the entire ELM2 (aa164-283) is required and sufficient for nuclear targetting of MIER1α and that a simple mutation, 214W→A in the ELM2 domain abolishes both the interaction between MIER1α and HDAC1/2 and its nuclear localization. Further investigation revealed that MIER1α is exported out of the nucleus when cells are treated with insulin, IGF-1, EGF or FGF, but not with 17β-estradiol, and this export out of the nucleus is mediated by CRM1. HDAC1 & 2 nuclear localization were not affected by MIER1α export, suggesting they are only involved in MIER1α nuclear import. Both Mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase B/Akt (PI3’K/AKT) pathways are activated upon treatment with growth factors, and it was further confirmed MIER1α nuclear export is triggered by the MAPK pathway, but not the PI3’K/AKT pathway. However, the mutation of predicted ERK1/2 consensus phosphorylation sites S10-P and/or S377-P motifs in the MIER1α sequence had no effect on its localization. MIER1α returns to the nucleus when activation of MAPK pathway diminishes, suggesting this process is transient and reversible. Deletion analysis narrowed the required sequence for export to the N-terminal region, aa1-163, containing acidic stretches. Overall, these results provide details of the mechanism responsible for MIER1α nucleocytoplasmic shuttling in a breast cancer carcinoma cell line; a similar mechanism may be operating during breast cancer progression.
3 citations
Journal Article•
TL;DR: The present data demonstrate for the first time the expression of an intracellular FGF in the bovine ovary and suggests that Fgf13 mRNA is upregulated in bovines theca cells during antral follicle growth.
Abstract: Recent studies have suggested a paracrine role for several fibroblast growth factors (FGFs) in the regulation of follicle and luteal development. Fgf13 is a non-secreted FGF that has been previously localized to the developing gonads, but it is not known if it is expressed in the adult ovary. The objective of the present study was to determine the expression pattern of Fgf13 mRNA in the bovine ovary. Fgf13 mRNA expression was examined by semiquantitative RT-PCR using Gapdh as the internal control gene in theca and granulosa cells, corpora lutea (CL) and oocytes collected from abattoir ovaries. Follicles were grouped according to estradiol content ( 20-100 and >100 ng/ml) and size (5-7, 8-10 and >10 mm diameter). CL samples were morphologically classified into four developmental stages. Fgf13 mRNA expression was assessed in pools containing 50 oocytes aspirated from follicles larger than 4 mm in diameter. ANOVA was used to test for the main effects of follicle size group, and estradiol concentration group in granulosa and theca cells, and to test the effect of CL developmental stage on Fgf13 mRNA abundance. Fgf13 mRNA was detected in the CL and in somatic follicle cells, but not in oocytes. Thecal Fgf13 expression increased with increasing follicle diameter but did not change with intrafollicular estradiol concentrations. No evidence of developmental regulation of Fgf13 mRNA expression was observed in granulosa cells and CL. The present data demonstrate for the first time the expression of an intracellular FGF in the bovine ovary and suggests that Fgf13 mRNA is upregulated in bovine theca cells during antral follicle growth.(AU)
3 citations
Cites background from "Fibroblast growth factors, their re..."
...…(FGFs 11, 12, 13, and 14) are unique in that they do not possess a signal sequence for secretion and are incapable of activating FGFRs (Smallwood et al., 1996; Olsen et al., 2003); these FGFs are termed FGF homologous factors or intracellular FGFs (iFGF; Powers et al., 2000; Itoh and Ornitz, 2008)....
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...A subfamily of FGFs joins the intracellular FGFs (iFGF), which are non-secreted proteins and thus expected to play different roles in relation to FGFs at the intracellular level (Smallwood et al., 1996; Powers et al., 2000; Itoh and Ornitz, 2008)....
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29 Jan 2015
TL;DR: Research progress is described on functional analyses of BmNPV genes that are involved in manipulating host physiology and behavior and comparative analyses of the genomes of B. mori and baculoviruses have revealed that the modern lepidopteran baculinuses may have acquired and modified several genes from an ancestral host insect to control the physiology of their own hosts and to increase the efficiency of virus transmission in nature.
Abstract: © 2015 TERRAPUB, Tokyo. All rights reserved. doi:10.5047/agbm.2015.00501.0001 (Keddie et al. 1989). At the late stage of infection, a markedly enhanced locomotion behavior of infected larvae is observed (Goulson 1997), which is followed by a dramatic degradation of the host cadaver. The Bombyx mori NPV (BmNPV), one of the wellcharacterized baculoviruses, is a virus specifically pathogenic for the domesticated silkworm B. mori. B. mori has been used for silk production for about 5,000 years. In addition to the large-scale propagation and use in silk production for the textile-industry, B. mori has recently become an important bioreactor for recombinant protein production. In Japan, two essential biotechnological methods have been developed; a system for transposon-based germline transformation in B. mori (Tamura et al. 2000) and a BmNPV-derived foreign gene expression system (Maeda et al. 1985). Maeda et al. (1985) developed a BmNPV expression vector that utilizes the strong promoter for the polyhedrin gene (polh) and reported a mass production of recombinant human α-interferon in silkworm (Maeda et al. 1985). This is the first report of a high level production of a foreign gene product in a living Abstract Nucleopolyhedroviruses (NPVs) belonging to the family Baculoviridae are large, enveloped, double-stranded DNA viruses that are pathogenic to insects. The Bombyx mori NPV (BmNPV) is an NPV pathogenic to the domesticated silkworm B. mori. DNA sequencing revealed that BmNPV potentially encodes 136 putative proteins. Mutagenesis experiments have discovered the viral proteins that control host catapillars at cellular and/or organismal levels: ecdysteroid UDP-glucosyltransferase inactivates an insect molting hormone ecdysone, protein tyrosine phosphatase is involved in wandering behavior at the late stage of infection, fibroblast growth factor induces host cell chemotaxis, and chitinase and cathepsin are required for postmortem host liquefaction. Furthermore, comparative analyses of the genomes of B. mori and baculoviruses have revealed that the modern lepidopteran baculoviruses may have acquired and modified several genes from an ancestral host insect to control the physiology of their own hosts and to increase the efficiency of virus transmission in nature. In this review, I describe our research progress on functional analyses of BmNPV genes that are involved in manipulating host physiology and behavior. Baculovirus Controls Host Catapillars by Manipulating Host Physiology and Behavior
3 citations
Cites background from "Fibroblast growth factors, their re..."
...The binding leads to receptor dimerization and auto-phosphorylation, and the activated FGFR then stimulates signal transduction pathways (Powers et al. 2000)....
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...The binding leads to receptor dimerization and auto-phosphorylation, and the activated FGFR then stimulates signal transduction pathways (Powers et al. 2000)....
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DOI•
01 Jan 2011
TL;DR: It is found that pi RNAs function through the PIWI, rather than the AGO, family Argonaute proteins, and the production of piRNAs requires neither microRNA (miRNA) nor small interfering RNA (siRNA) pathway machinery, allowing the discovery of the third conserved small RNA silencing pathway.
Abstract: In the Drosophila germ line, PIWI-interacting RNAs (piRNAs) ensure genomic stability by silencing endogenous selfish genetic elements such as retrotransposons and repetitive sequences. We examined the genetic requirements for the biogenesis and function of piRNAs in both female and male germ line. We found that piRNAs function through the PIWI, rather than the AGO, family Argonaute proteins, and the production of piRNAs requires neither microRNA (miRNA) nor small interfering RNA (siRNA) pathway machinery. These findings allowed the discovery of the third conserved small RNA silencing pathway, which is distinct from both the miRNA and RNAi pathways in its mechanisms of biogenesis and function. We also found piRNAs in flies are modified. We determined that the chemical structure of the 3´-terminal modification is a 2´- O -methyl group, and also demonstrated that the same modification occurs on the 3´ termini of siRNAs in flies. Furthermore, we identified the RNA methyltransferase Drosophila Hen1, which catalyzes 2´- O -methylation on both siRNAs and piRNAs. Our data suggest that 2´- O -methylation by Hen1 is the final step of biogenesis of both the siRNA pathway and piRNA pathway. Studies from the Hannon Lab and the Siomi Lab suggest a ping-pong amplification loop for piRNA biogenesis and function in the Drosophila germline. In this model, an antisense piRNA, bound to Aubergine or Piwi, triggers production of a sense piRNA bound to the PIWI protein Argonaute3 (Ago3). In turn, the new piRNA is envisioned to produce a second antisense piRNA. We isolated the loss-of-function mutations in ago3 , allowing a direct genetic test of this model. We found that Ago3 acts to amplify piRNA pools and to enforce on them an antisense bias, increasing the number of piRNAs that can act to silence transposons. Moreover, we also discovered a second Ago3-independent piRNA pathway in somatic ovarian follicle cells, suggesting a role for piRNAs beyond the germ line.
3 citations
Cites background from "Fibroblast growth factors, their re..."
...Within this signaling arm, activation of a MAPK protein, extracellular signal regulated protein kinase (ERK), eventually leads to gene regulation through the modification of transcription factors (Dailey et al., 2005; Powers et al., 2000; Tsang and Dawid, 2004)....
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References
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TL;DR: It is demonstrated that free heparin and heparan sulfate can reconstitute a low affinity receptor that is, in turn, required for the high affinity binding of bFGF.
2,448 citations
TL;DR: This work highlights conserved protein domains that act as key regulatory participants in many of these different signalling pathways in multicellular organisms.
Abstract: Communication between cells assumes particular importance in multicellular organisms. The growth, migration and differentiation of cells in the embryo, and their organization into specific tissues, depend on signals transmitted from one cell to another. In the adult, cell signalling orchestrates normal cellular behaviour and responses to wounding and infection. The consequences of breakdowns in this signalling underlie cancer, diabetes and disorders of the immune and cardiovascular systems. Conserved protein domains that act as key regulatory participants in many of these different signalling pathways are highlighted.
2,433 citations
"Fibroblast growth factors, their re..." refers background in this paper
...One way these recruited target proteins may be localized to the activated receptor is through the interaction between their Src-homology 2 (SH2) domains and specific phosphotyrosine residues on the activated receptor (Pawson 1995)....
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...Phosphorylated tyrosine residues, in turn, recruit other signaling molecules to the activated receptors and propagate the signal through many possible transduction pathways (Pawson 1995)....
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TL;DR: Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of Thalidomid-treated embryos.
Abstract: Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.
2,364 citations
TL;DR: It is demonstrated that FGF 1 is the only FGF that can activate all FGF receptor splice variants and the relative activity of all the other members of the FGF family is determined.
2,066 citations
"Fibroblast growth factors, their re..." refers background in this paper
...†From Ornitz et al. (1996), except where stated; ‡From Koga et al. (1995); §From Miralles et al. (1999); ¶From Xu et al. (1999). topologically identical to interleukin-1β (IL-1β) (Zhu et al. 1991), with which some members also share the feature of secretion by an endoplasmic reticulum…...
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...Mutation of all four cysteines to serines results in a protein with the same secondary structure and equally mitogenic for 3T3 cells as the wild-type FGF-2 (Foxet al. 1988), suggesting that the formation of disulfide bridges is not important for the secondary structure and mitogenic activity of…...
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...Ornitz et al. (1996) determined the specificity of different FGFs for different receptor isoforms by overexpressing these isoforms in Baf3 cells, which do not normally express FGFRs, and assaying for [3H]thymidine incorporation in these cells following treatment with different FGFs (see Table 2)....
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...1, IIIb 100 60 34 16 4 5 6 4 4 1, IIIc 100 104 0 102 59 55 0 1 21 2, IIIb 100 9 45 15 5 5 81 4 7 2, IIIc 100 64 4 94 25 61 2.5 16 89 3, IIIb 100 1 2 1 1 1 1 1 42 3, IIIc 100 107 1 69 12 9 1 41 96 4 100 113 6 108 7 79 2 76 75 Modified from Ornitz et al. (1996)....
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1,994 citations
"Fibroblast growth factors, their re..." refers background in this paper
...Defining features of the FGF family are a strong affinity for heparin and HLGAGs (Burgess & Maciag 1989), as well as a central core of 140 amino acids that is highly homologous between different family members....
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