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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01 Jan 2011
TL;DR: Retroviral insertional mutagenesis (IM) screens provide one of the most efficient tools to identify genes involved in tumorigenesis and from there the specific oncogenic pathways involved.
Abstract: Transformation of a normal cell into a cancer cell requires sequential accumulation of several genetic changes that affect various collaborating signaling cascades mainly involved in cell proliferation, survival and development [46] To develop novel specific therapeutic compounds for cancer treatment, identification of these cancer causing genes, and subsequently the oncogenic pathways in which these genes act, is of utmost importance Although a great deal of insight in the cellular mechanisms that lead to cancer has been obtained, many key players are still unidentified Retroviral insertional mutagenesis (IM) screens provide one of the most efficient tools to identify genes involved in tumorigenesis and from there the specific oncogenic pathways involved
1 citations
01 Jan 2009
TL;DR: The role of Shh in this process is indirect, and is mediated by its effect on Fgf signaling, which is essential for survival of cells during development in neural-plate derived tissues such as the retina and the neural tube.
Abstract: The development of multicellular organisms depends on the integration between pattern formation and the regulation of cell number. The secreted signaling protein Sonic Hedgehog (Shh) has been implicated in directing both of these processes, suggesting it may participate in achieving this integration. The role of Shh in directing pattern formation in vertebrate model systems, including the zebrafish, has been well characterized during the last decades. Among the organs in which the patterning function of Shh has been best studied are the limb buds, the retina, and the neural tube. I therefore chose to study the role of Shh in regulating cell proliferation, cell death, and cell survival in these organs of the zebrafish. In addition, I also examined the interaction between Shh and several other factors directing cell proliferation and cell death, including the secreted signaling protein Fgf, and the transcription factor p53. In the context of the zebrafish paired fin buds, I focused on the interplay between Shh and the Fgf signaling pathways. Shh directs pattern formation along the anterior/posterior axis of the vertebrate limb, whereas several Fgfs in combination direct pattern formation along the proximal/distal axis of the limb. In addition, Shh and Fgf signaling pathways in the limb bud are mutually interdependent. Therefore, I aimed to determine the relative importance of each pathway for proliferation in this organ. In zebrafish shh mutants, both proliferation and Fgf signaling in the pectoral fin buds are initially normal, but later are strongly reduced. Furthermore, pharmacological inhibition of Hh signaling for short periods has little effect on either Fgf signaling, or on cell-cycle gene expression, whereas long periods of inhibition lead to the downregulation of both. By contrast, even short periods of pharmacological inhibition of Fgf signaling lead to strong disruption of proliferation in the fin buds, without affecting Shh signaling. Activation of Fgf signaling by implantation of FGF4-soaked beads into shh mutant pectoral fin buds leads to the rescue of cell-cycle gene expression and proliferation in these organs. These results show that the role of Shh in this process is indirect, and is mediated by its effect on Fgf signaling. By contrast, the activity of the Fgf pathway affects proliferation directly and independently of its effect on Shh. In neural-plate derived tissues such as the retina and the neural tube, Shh is essential for survival of cells during development. Here I identify p53 as the mediator of cell death in shh mutant since in the absence of Shh activity, p53 target genes are induced, and p53 loss leads to suppression of apoptosis in shh mutants. p53 induces apoptosis in the absence of Shh signaling by activating expression of the pro-apoptotic target genes puma and bax1, which induce the intrinsic pathway of apoptosis and whose level of expression correlates with the severity of apoptotic phenotypes. In support of the hypothesis that p53 activation results from loss of Shh signaling, p53 target gene expression and apoptosis are both suppressed by over-expression of dominant-negative PKA in shh mutants. To monitor p53 activation in living zebrafish embryos, I constructed a transgenic line expressing fluorescent protein under the control of the p53-driven promoter. Indeed, p53 reporter expression correlates very well with apoptosis levels in vivo, except in the early retina. Furthermore, p53 reporter can be induced by genotoxic drugs and colocalises with active-Caspase3. p53 reporter-positive cells were also found defective in their cell cycle progression at 48 hpf. Consistent with this result, proliferation assays on the double shh p53 mutant revealed that loss of p53 rescues normal cell-cycle exit and increases the rate of mitosis in the shh mutant retina. Moreover, differentiation of amacrine cells and photoreceptors was rescued in the double shh p53 mutant retina. These results show that in the absence of shh, p53 is required for the induction of apoptosis, and also regulates proliferation, cell-cycle exit and differentiation in the retina. Taken together, my results show that Shh plays an important role in regulating both proliferation and cell survival during vertebrate development, and that it affects these processes distinctly in different tissues. In the context of the paired fin buds Shh directs pattern formation and in addition promotes cell proliferation, via activation of the Fgf signaling pathway. In neural-plate derived tissues Shh not only plays a patterning role, but also promotes cell survival and proliferation by antagonizing activation of the transcription factor p53.
1 citations
Cites background from "Fibroblast growth factors, their re..."
...Indeed, Fgf1 and Fgf2 were initially identified as mitogenic factors in fibroblast tissue culture, and subsequently, other members of the FGF protein family were found to have a similar activity (Powers et al., 2000)....
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TL;DR: The role of phosphatonins in Pi metabolism in normal and pathologic conditions is reviewed and the correlations among the various phosphaton ins are investigated to investigate the correlations between the various phosphate-regulating peptides.
Abstract: Phosphorus (Pi) plays an important role in nucleic acid synthesis, energy metabolism, bone mineralization and cell signaling, and is also present in sugars, phospholipids and phosphoproteins. Phosphate homeostasis is controlled by processes that regulate the intestinal absorption and renal excretion of Pi, and bone turnover. These processes are influenced by peptide and sterol hormones, such as parathyroid hormone and 1α,25-dihydroxyvitamin D (1α,25[OH]2D3). Recently, a new class of phosphate-regulating peptides has been discovered: phosphatonins. These factors, such as FGF-23, secreted frizzled-related protein-4, matrix extracellular phosphoglycoprotein and FGF-7, are circulating peptides with potent phosphaturic activity. These peptides inhibit Na/Pi transporters in renal epithelial cells and, therefore, increase renal Pi excretion. In addition, FGF-23 and secreted frizzled-related protein-4 inhibit 25-hydroxyvitamin D 1α-hydroxylase activity, reducing 1α,25(OH)2D3 synthesis and, thus, intestinal Pi abs...
1 citations
Dissertation•
01 Jan 2013
TL;DR: The regulation of the presented nuclear body and protein complexes influences neuronal differentiation and neurite outgrowth in vitro and in vivo, and there is evidence to suggest that neuronal differentiation is likewise affected by diffuse nucleoplasmic coilin.
Abstract: Spinal muscular atrophy (SMA) is a
neurodegenerative disease, caused by reduced levels of the survival of
motoneuron (SMN) protein. How SMN is involved in maintaining motoneuron integrity
is unknown, so far. In the nucleus, SMN is associated to two compartments
called nuclear gems and Cajal bodies (CBs). The binding of SMN to Cajal
bodies occurs by a direct interaction with the CB marker protein coilin. Although the major amount of coilin is located diffuse in the nucleus outside of CBs, SMN and coilin are essential for maturation of small nuclear ribonucleoprotein particles (snRNPs) inside Cajal bodies. There,
three single snRNPs are assembled to one tri-snRNP, a subunit of the spliceosom.
Another direct binding partner of nuclear SMN is the
23 kDa isoform of fibroblast growth factor – 2 (FGF-223). The
FGF-223/SMN interaction is already known to destabilize nuclear
gems, the second nuclear compartment SMN is associated to. By using fluorescence recovery after photobleaching (FRAP) and
photoconversion experiments in the present study of Forthmann et al.,
2013 (Chapter I), we have discovered that FGF-223/SMN
complex formation leads to a release of immobile SMN from CBs, followed by
snRNP accumulation. Thus, tri-snRNP assembly at Cajal bodies seems to be
associated with immobile SMN. In an unpublished study of Forthmann et al.
(Chapter II), we show that co-expression of FGF-223 and SMN
inhibits both FGF-223- dependent transcription and SMN promoted
neurite outgrowth. Hence, we propose a model in which FGF-223
and SMN form an inactive complex, antagonizing both protein functions.
Moreover, there is evidence to suggest that neuronal differentiation is
likewise affected by diffuse nucleoplasmic coilin. Endogenous coilin levels
decrease during differentiation of human neuroblastoma cells (NB), as it is
already pointed out for murine PC12 cells. Expression of coilin reduces
neurite outgrowth, indicating a new function of this protein in inhibition of
neuronal differentiation. While SMN has coilin and FGF-223 as
interaction partners, among others, FGF-223 has another nuclear
binding partner beside SMN: the fibroblast growth factor receptor 1 (FGFR1).
FGF-223/FGFR1 interaction heightens neuronal differentiation by
inducing a pathway called integrative nuclear FGFR1
signaling (INFS). The INFS activates the tyrosine
hydroxylase (TH) gene. During the development of TH-positive cells in the
ventral midbrain (VM) of embryonic mice, the FGFR1
builds a nuclear complex with the orphan nuclear receptor Nurr1, as we could
demonstrate in the study of Baron et al., 2012
(Chapter III). FRAP experiments reveal a dynamic
change: FGFR1 is slowed down by interaction with Nurr1 into a chromatin-bound
fraction. The TH gene promoter is activated by FGFR1/Nurr1 complex formation,
similar to the FGFR1/FGF-223 binding. In conclusion, the regulation of the
presented nuclear body and protein complexes influences neuronal
differentiation and neurite outgrowth in vitro and in vivo. We
assume the nuclear architecture to be relevant in differentiation processes
of developing neuronal cells and therefore to be a possible target in
neurodegenerative and neurodevelopmental disorders.
1 citations
Cites background from "Fibroblast growth factors, their re..."
...A receptor called FGFR5, also referd to as fibroblast growth factor receptor like 1 (FGFRL1), is lacking a tyrosine kinase domain (Powers et al. 2000; Schlessinger 2000; Wiedemann and Trueb 2000)....
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Book•
15 May 2009
TL;DR: Proteins important for tumor angiogenesis and invasion were detected in hypoxic brain foci identified by SPAT and were elevated compared with control brain and it was shown that HIF-1α, MMP-9, VEGF-A, and VEGFR2 protein and mRNA expression levels were higher in brain tumor tissues compared to normal brain.
Abstract: Role of Hypoxia and Hypoxia-induced Factors in the Development of Breast Cancer Brain Metastasis. (August 2008) Gina Florentina Lungu, B.S., University of Bucharest; M.S., Texas Woman’s University Chair of Advisory Committee: Dr. Gheorghe Stoica Here we studied the role of hypoxia and hypoxia-induced factors in the development of breast cancer brain metastasis by using ENU1564, a carcinogen-induced mammary adenocarcinoma cell line. We detected hypoxia noninvasively by using a novel spectroscopic photoacoustic tomography technology (SPAT). Sprague-Dawley rats inoculated intracranially with ENU1564, a carcinogen-induced rat mammary adenocarcinoma cell line, were imaged with SPAT three weeks post inoculation. Proteins important for tumor angiogenesis and invasion were detected in hypoxic brain foci identified by SPAT and were elevated compared with control brain. We showed that HIF-1α, MMP-9, VEGF-A, and VEGFR2 (Fkl-1) protein and mRNA expression levels were higher (P < 0.05) in brain tumor tissues compared to normal brain. We also found an increased expression of HIF-1α proteins, MMP-9, VEGF-A and VEGFR2 mRNA and proteins in hypoxic ENU1564 cells in vitro. We also demonstrated the involvement of PI3K-Akt pathway in hypoxic regulation of MMP-9 and VEGF but not VEGFR2 by using specific PI3K inhibitor. Using MEK1/2
1 citations
Cites background or result from "Fibroblast growth factors, their re..."
...Fibroblast growth factors (FGFs) and FGF signaling pathways appear to play significant roles not only in normal development and wound healing, but also in resistance to cell death, increased motility and invasiveness, increased angiogenesis, enhanced metastasis, and resistance to chemotherapy and radiation, all of which can enhance tumor progression and clinical aggressiveness [36]....
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...proliferation, and survival in a variety of cells [36]....
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...Consistent with current literature [36,127], we observed that ENU1564 breast cancer...
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...Ultimately, activation of FGF receptors leads to signal transduction through multiple pathways including mitogen-activated protein kinases (MAPK), phosphatidylinositol 3-kinase (PI3K), phospholipase Cγ (PLCγ) [36, 37], leading to cell...
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...Ultimately, activation of FGF receptors leads to signal transduction through multiple pathways including mitogen-activated protein kinases (MAPK), phosphatidylinositol 3-kinase (PI3K), phospholipase Cγ (PLCγ) [36, 37], leading to cell proliferation, and survival in a variety of cells [36]....
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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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