Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Basic fibroblast growth factor (bFGF) is an autocrine growth factor that is overexpressed in glial tumor cells and promotes their unregulated proliferation. We have previously reported that increased messenger RNA (mRNA) stability contributes to the elevated steady state levels of bFGF mRNA in human U87-MG glioma cells. Stability of bFGF mRNA is regulated by a natural antisense transcript in Xenopus oocytes, but the mammalian equivalent of this transcript has not previously been described. We were interested in identifying the human equivalent of this antisense transcript in order to study its role in bFGF mRNA stability. Analysis of the 3'-untranslated region of the 6.7-kilobase human bFGF mRNA revealed two areas of greater than 75% homology to exons 3 and 4 of the Xenopus antisense transcript, separated by 4300 basepairs of nonhomologous sequence. We used reverse transcription-polymerase chain reaction to amplify, clone, and sequence a 301-basepair fragment of the antisense splice variant from U87-MG cells. The clone (gfg-1) is 73% identical to the Xenopus sequence, with a conserved splice junction and an open reading frame. Strand-specific gfg-1 complementary RNA probes detect a 1.5-kilobase mRNA transcript in normal rat tissues and human T47D breast cancer cells, which contain very low levels of bFGF mRNA. In contrast, antisense transcript expression was undetectable by Northern hybridization in U87-MG cells, which overexpress the bFGF sense mRNA. The reciprocal relationship between bFGF sense and antisense expression suggests that antisense transcripts may regulate bFGF expression in mammalian cells, and that disruption of normal sense/antisense mRNA ratios may lead to overexpression of bFGF in some tumors.
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PMID:Identification and characterization of an antisense RNA transcript (gfg) from the human basic fibroblast growth factor gene. 798 47

Glia cell line-derived neurotrophic factor (GDNF), a recently cloned member of the transforming growth factor-beta (TGF-beta) superfamily, has been implicated in the survival, morphological and functional differentiation of midbrain dopaminergic neurons and motoneurons in vitro and in vivo. The factor may thus have utility in the treatment of various human neurodegenerative disorders. Mechanisms regulating expression of GDNF in normal and diseased brain as a possible means to increase the local availability of GDNF are only beginning to be explored. We have established and employed a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) to study and compare levels of expression of GDNF mRNA in several cell types and to investigate its regulation. GDNF expression was clearly evident in primary cultured astrocytes, the glioma B49 and C6 cell, but less pronounced in the Schwannoma RN22 cell lines. Little or no signal could be observed in neuroblastoma cell lines (IMR32, LAN-1) or the pheochromocytoma cell line PC12, emphasizing the glial character of this factor. Using the C6 cell line we found that fibroblast growth factor-2 (FGF-2; bFGF) can increase GDNF mRNA levels, whereas FGF-1, platelet-derived growth factor (PDGF), and vasoactive intestinal polypeptide (VIP) are apparently ineffective. Several other factors (forskolin, kainic acid, triiodothyronine dexamethasone, GDNF, TGF-beta 1, and interleukin-6) appear to have slightly negative effects on GDNF mRNA levels at the concentrations tested. To further explore the relationship between FGF-2 and GDNF, we also addressed the question whether GDNF, like FGF-2, may have an effect on C6 cell proliferation. We conclude that (1) glial and glial tumor cells, rather than neuronal cell lines, express GDNF, (2) that FGF-2 has a prominent inductive effect on GDNF expression and (3) that GDNF stimulates C6 cell proliferation. Finally, these data suggest that neurotrophic actions of FGF-2 in mixed glial-neuronal cell cultures might be mediated in part by GDNF.
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PMID:GDNF mRNA levels are induced by FGF-2 in rat C6 glioblastoma cells. 888 50

FGF-2 has been implicated in the neoplastic transformation of glioma cells and in the transition of normal quiescent astrocytes to a proliferating, reactive state. In the present study we have observed that in human glial cells, levels and subcellular localization of FGF-2 are different in quiescent and proliferating cells. FGF-2 was detected in the cytoplasm of non-reactive astrocytes in human brain sections. In contrast FGF-2 was located within the cytoplasm and nuclei of reactive astrocytes in gliotic brain tissue and in neoplastic cells of glioma tumors. In vitro, FGF-2 was found predominantly in the nucleus of subconfluent proliferating astrocytes, but was detected only in the cytoplasm of density arrested quiescent astrocytes. Our results suggest that reduced cell contact stimulates nuclear accumulation of FGF-2, accompanying mitotic activation of reactive human astrocytes. FGF-2 was constitutively localized to the nucleus of continuously proliferating glioma cells independent of cell density. A role for intracellular FGF-2 was further suggested by the observation that glioma cells that are not stimulated to proliferate by extracellular FGF-2 proliferated faster when transfected with FGF-2 expressing vectors. This increased proliferation correlated with nuclear accumulation of FGF-2. Cell proliferation was attenuated by 5'-deoxy-5'-methylthioadenosine, a FGF-2 receptor tyrosine kinase inhibitor that acts within the cell, but was unaffected by myo-inositol hexakis [dihydrogen phosphate] that disrupts FGF-2 binding to plasma membrane receptors. Our results indicate that FGF-2 serves as a nuclear regulator of proliferation in astrocytic cells. In glioma cells, the constitutive presence of FGF-2 in the nucleus may promote proliferation that is insensitive to cell contact inhibition.
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PMID:Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells. 901 Feb 19

Basic fibroblast growth factor (FGF-2) is abundant in the developing and adult brain and has been linked with the origin and growth of neuronal and glial cells. Glial cells produce high levels of FGF-2, stimulating autocrine growth as well as the survival and function of neurons in a paracrine manner. Abnormal levels of FGF-2 have been linked with Alzheimer's, Huntington's, and Parkinson's diseases. Recent evidence has suggested that a component of the mitogenic response of glial cells is exerted on FGF-2 at the transcriptional level. To assess transcriptional regulation of this potent growth factor, we cloned a 1.4-kb genomic fragment containing the rat FGF-2 promoter region. DNA blotting results indicated that the rat FGF-2 gene exists as a single copy in the genome. The promoter region contains no TATA box but appears to rely instead on multiple GC-rich start sites (P0, P1, and P2) for transcription initiation in rat brain as well as C6 glioma cells. One of these sites (P0) was located within four nucleotides of the reported 5' end of the rat brain cDNA and constituted part of a consensus Egr-1 binding site (5'-GCGGGGGCG-3'). Transcription from this site could be stimulated in C6 glioma cells in response to phorbol ester treatment. The induction of a "new" site (P1) with phorbol ester also suggested a mechanism to explain the discrepancy between the reported "starts" for the ovarian versus brain cDNAs. A hybrid luciferase gene directed by rat FGF-2 5'-flanking DNA (-1,058/+54) was expressed in rat glioma C6, heart myoblast H9c2, and human astrocytoma U87-MG cells after gene transfer. The level of transfected FGF-2 promoter activity was higher in glial cells (C6 and U87-MG) compared with nonglial (H9c2) cells. Also, expression of this hybrid FGF-2/luciferase gene was increased in response to phorbol ester or serum treatment of C6 cells. Deletion analysis revealed the presence of both positive and negative regulatory regions that are involved in the transcriptional control of rat FGF-2 gene by mitogenic stimuli.
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PMID:Cloning of the rat fibroblast growth factor-2 promoter region and its response to mitogenic stimuli in glioma C6 cells. 904 34

In this study we describe the presence of high affinity FGF-2 binding sites in the nuclei of U251MG glioma cells (K(d)=7 pM). Immunoprecipitation of total cell extracts with FGF receptor (FGFR) 1-4 antibodies showed that U251MG glioma cells express only FGFR1. [125I]FGF-2 cross linking to nuclear extracts followed by FGFR1 immunoprecipitation showed that FGFR1 may account for the nuclear FGF-2 binding sites. Western blot analysis demonstrated the presence of 103, 118 kDa and small amounts of 145 kDa FGFR1 isoforms in the nuclei of glioma cells. All isoforms contain both the C- and N-terminal domains. Nuclear FGFR1 retains kinase activity. Immunocytochemistry using confocal microscopy showed specific FGFR1 immunoreactivity within the nuclear interior. In continuously proliferating glioma cells, nuclear FGFR1 is constitutively expressed, independent of cell density. In contrast, in nontransformed human astrocytes, nuclear FGFR1 levels fluctuate with the proliferative state of the cell. In quiescent, confluent astrocytes nuclear FGFR1 protein was depleted. An accumulation of nuclear FGFR1 was observed following the transition to a subconfluent, proliferating state. Transfection of a pcDNA3.1-FGFR1 expression vector into glioma cells that do not express FGFR1 resulted in the nuclear accumulation of FGFR1, increased cell proliferation, and stimulated transition from the G0/G1 to the S-phase of the cell cycle. The increased proliferative rate was resistant to inhibition by the cell-impermeable FGF binding antagonist, myoinositol hexakis [dihydrogen phosphate]. Our results suggest that the constitutive nuclear presence of FGFR1 contributes to the increased proliferation of glioma cells while the transient nuclear accumulation of FGFR1 in normal astrocytes may play a role in the transition to a reactive state.
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PMID:Nuclear accumulation of fibroblast growth factor receptors in human glial cells--association with cell proliferation. 917 56

Fibroblast growth factor (FGF) signaling has been recognized in human gliomas. We tested the effect of FGF-2 and FGF-9 on the proliferation and the expression of matrix metalloproteinases (MMPs) and their inhibitor (TIMP-1) in vitro. Both FGFs showed mitogenic activity on U251MG and NMC-G1 cells. MMP-1 expression and collagenolytic activity of NMC-G1 but not of U251MG, and TIMP-1 expression of both cells were stimulated by FGFs. MMP-2 expression, gelatinolytic activity, and chemoinvasion on the matrigel were not altered. FGFs may regulate proliferation and microenvironmental factors independently in each glioma type.
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PMID:Fibroblast growth factor-2 and -9 regulate proliferation and production of matrix metalloproteinases in human gliomas. 953 33

Basic fibroblast growth factor (FGF-2) and high affinity FGF receptor (FGFR) have been detected in the nucleus as well as the cytoplasm of many human gliomas, and are known to stimulate cellular proliferation and angiogenesis in the tumors. To investigate the effects of inactivation of FGFR on the growth of malignant gliomas, we constructed a replication-deficient recombinant adenovirus vector encoding a truncated form of chicken FGFR1 (AxCA delta FR). AxCA delta FR-infected cells were confirmed to express truncated FGFR protein by immunoblotting and FGF-2-dependent clonogenicity of NIH3T3 cells was suppressed by infection with this virus vector. Then human malignant glioma cell lines U-251MG and T98G, both of which have been reported to express FGF-2 and FGFR, were infected with AxCA delta FR. These infected cells showed nuclear as well as cytoplasmic expression of a truncated FGFR protein. Proliferation rate and the ability to form colonies in soft agar of the cells infected with this virus vector were significantly suppressed compared with those of uninfected and lacZ-expressing adenovirus-infected cells. Moreover, intratumoral injection of AxCA delta FR significantly suppressed the subcutaneous tumor growth of the glioma cells in nude mice. We concluded that inactivation of the cytoplasmic and nuclear FGFR using this truncated FGFR-expressing adenovirus vector can inhibit the growth of malignant gliomas both in vitro and in vivo.
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PMID:Adenovirus-mediated gene transfer of a truncated form of fibroblast growth factor receptor inhibits growth of glioma cells both in vitro and in vivo. 1072 Jan 99

Several members of the fibroblast growth factor (FGF) family lack signal peptide (SP) sequences and are present only in trace amounts outside the cell. However, these proteins contain nuclear localization signals (NLS) and accumulate in the cell nucleus. Our studies have shown that full length FGF receptor 1 (FGFR1) accumulates within the nuclear interior in parallel with FGF-2. We tested the hypothesis that an atypical transmembrane domain (TM) plays a role in FGFR1 trafficking into the nuclear interior. With FGFR1 destined for constitutive fusion with the plasma membrane due to its SP, how the receptor may enter the nucleus is unclear. Sequence analysis identified that FGFR1 has an atypical TM containing short stretches of hydrophobic amino acids (a.a.) interrupted by polar a.a. The beta-sheet is the predicted conformation of the FGFR1 TM, in contrast to the alpha-helical conformation of other single TM tyrosine kinase receptors, including FGFR4. Receptor trafficking in live cells was studied by confocal microscopy via C-terminal FGFR1 fusions to enhanced green fluorescent protein (EGFP) and confirmed by subcellular fractionation and Western immunoblotting. Nuclear entry of FGFR1-EGFP was independent of karyokinessis, and was observed in rapidly proliferating human TE671 cells, in slower proliferating glioma SF763 and post-mitotic bovine adrenal medullary cells (BAMC). In contrast, a chimeric FGFR1/R4-EGFP, where the TM of FGFR1 was replaced with that of FGFR4, was associated with membranes (golgi-ER, plasma, and nuclear), but was absent from the nucleus and cytosol. FGFR1delta-EGFP mutants, with hydrophobic TM a.a. replaced with polar a.a., showed reduced association with membranes and increased cytosolic/nuclear accumulation with an increase in TM hydrophilicity. FGFR1(TM-)-EGFP (TM deleted), was detected in the golgi-ER vesicles, cytosol, and nuclear interior; thus demonstrating that the FGFR1 TM does not function as a NLS. To test whether cytosolic FGFR1 provides a source of nuclear FGFR1, cells were transfected with FGFR1(SP-) (SP was deleted), resulting in cytosolic, non-membrane, protein accumulation in the cytosol and the cell nucleus. Our results indicate that an unstable association with cellular membranes is responsible for the release of FGFR1 into the cytosol and cytosolic FGFR1 constitutes the source of the nuclear receptor.
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PMID:Nuclear trafficking of FGFR1: a role for the transmembrane domain. 1264 9

Fibroblast growth factor-2 (FGF-2) is a potent heparin-binding protein with growth-promoting and anti-apoptotic activity. Transcription of the GFG/NUDT6 gene on the opposite DNA strand generates an overlapping antisense RNA (FGF-AS) implicated in the post-transcriptional regulation of FGF-2. C6 glioma cells coordinately express FGF-2 and FGF-AS mRNA in a cell cycle-dependent manner. Cellular FGF-2 immunoreactivity was also cell cycle-dependent, with marked nuclear accumulation during S-phase. Stable transfection and overexpression of the FGF-AS RNA resulted in suppression of total cellular FGF-2, and a reduction in nuclear accumulation of FGF-2 isoforms. Serum stimulation of growth-arrested wild-type cells evoked a rapid nuclear translocation of FGF-2, and cell cycle re-entry. FGF-AS transfectants, in contrast, showed a significant delay in recovery of both nuclear FGF-2 staining and S-phase re-entry. Similar results were observed when cells were released from aphidicolin-induced G1 arrest or subjected to heat shock. These findings indicate that FGF-AS RNA inhibits expression and cell cycle-dependent nuclear accumulation of FGF-2, and this is associated with a marked delay in S-phase progression. The results suggest that the endogenous FGF antisense RNA may play a significant functional role in the regulation of FGF-2 dependent cell proliferation in FGF-2 expressing cells.
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PMID:The fibroblast growth factor-2 antisense gene inhibits nuclear accumulation of FGF-2 and delays cell cycle progression in C6 glioma cells. 1730 51

Thalidomide is considered to be a potent antiangiogenic and immunomodulatory drug for cancer therapy. Earlier clinical studies have found that patients responding to this drug often had high plasma levels of basic fibroblast growth factor (bFGF). This cytokine is a proangiogenic factor overexpressed in many tumors and is also a regulator of limb development; hence, it might be a target of thalidomide. Using U-87 MG cell lines, we found that thalidomide, especially when encapsulated in a liposome, down-regulated the transcription and translation of the FGF-2 gene by interacting with G-rich regions present in the promoter and the internal ribosome entry site of its transcript at concentrations much lower than therapeutic serum concentrations. Thalidomide treatment also dramatically suppressed the anchorage-independent growth of U-87 MG and other glioma cells by over a thousand fold without affecting its anchorage-dependent growth, which may be accomplished by knocking down endogenous bFGF expression in these cells. Accordingly, the addition of recombinant bFGF partially restored the anchorage-independent growth of these cells. Our data suggest that by targeting the G-rich regions of bFGF, thalidomide (at 0.1 microg/mL) can reduce cellular bFGF levels and affect tumor anchorage-independent growth, the hallmark of tumorigenicity. Our results are promising for future clinical investigations using low doses of thalidomide.
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PMID:The G-rich promoter and G-rich coding sequence of basic fibroblast growth factor are the targets of thalidomide in glioma. 1868 60


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