Localization of basic fibroblast growth factor and its mRNA after CNS injury

Frautschy, Sally A.; Walicke, Patricia A.; Baird, Andrew

doi:10.1016/0006-8993(91)90837-l

Cited by 202 publications

(83 citation statements)

References 35 publications

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“…Neurotrophic factors are produced around the locus of CNS lesions, and although earlier studies did not identify the source of these factors (NietoSampedro et al, 1982(NietoSampedro et al, , 1983Needels et al, 1986;Ernfors et al, 1989;Ishikawa et al, 1991;Lindvall et al, 1994), more recent studies have documented the upregulation of nerve growth factor (NGF) (Bakhit et al, 1991;Altar et al, 1992;Oderfeld-Nowak et al, 1992;Arendt et al, 1995), ciliary neurotrophic factor (Ip et al, 1993;Asada et al, 1995;Wen et al, 1995), basic fibroblast growth factor (Finklestein et al, 1988;Frautschy et al, 1991;GomezPinilla et al, 1995;Wen et al, 1995), and insulin-like growth factor-1 (Komoly et al, 1992) in reactive astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Astrogliosis in the Neonatal and Adult Murine Brain Post-Trauma: Elevation of Inflammatory Cytokines and the Lack of Requirement for Endogenous Interferon-γ

et al. 1997

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The relevance of astrogliosis remains controversial, especially with respect to the beneficial or detrimental influence of reactive astrocytes on CNS recovery. This dichotomy can be resolved if the mediators of astrogliosis are identified. We have measured the levels of transcripts encoding inflammatory cytokines in injury systems in which the presence or absence of astrogliosis could be produced selectively. A stab injury to the adult mouse brain using a piece of nitrocellulose (NC) membrane elicited a prompt and marked increase in levels of transcripts for interleukin (IL)-1α, IL-1β, and tumor necrosis factor (TNF)-α, which are considered to be microglia/macrophage cytokines. The elevations preceded, or occurred concomitantly with, the rise in glial fibrillary acidic protein mRNA, an early manifestation of astrogliosis. In neonatal mice, IL-1 and TNF-α mRNA were elevated to a greater extent by an NC-implant injury, which produced astrogliosis, than after an NC-stab, with minimal astrogliosis. We determined whether endogenous interferon (IFN)-γ could be responsible for the observed increases in IL-1 and TNF-α, because IFN-γ is a potent microglia/macrophage activator, and because its exogenous administration to rodents enhanced astrogliosis after adult or neonatal insults. A lack of requirement for endogenous IFN-γ was demonstrated by three lines of evidence. First, no increase in IFN-γ transcripts could be found at injury. Second, the administration of a neutralizing antibody to IFN-γ did not attenuate astrogliosis. Third, in IFN-γ knockout adult mice, astrogliosis and increases in levels of IL-1α and TNF-α were induced rapidly by injury. The marked elevation of inflammatory cytokines is discussed in the context of astrogliosis and general CNS recovery.

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Section: Discussionmentioning

confidence: 99%

Astrogliosis in the Neonatal and Adult Murine Brain Post-Trauma: Elevation of Inflammatory Cytokines and the Lack of Requirement for Endogenous Interferon-γ

et al. 1997

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“…In normal adult rat brain astrocytes express low levels of FGF-2 protein. During gliosis, however, the number of astrocytes expressing FGF-2 increases dramatically along with the levels of FGF-2 protein and mRNA (Finkelstein et al, 1988;Frautschy et al, 1991;Liu and Chen, 1994;Gomez-Pinilla et al, 1992) and correlates with their proliferation (Liu and Chen, 1994). The autocrine action of FGF-2 has also been implicated in the abnormal growth of the transformed astrocytes in human brain neoplasms.…”

Section: Introductionmentioning

confidence: 99%

Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells

et al. 1997

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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 di erent 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 subcon¯uent 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 una ected 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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“…In the normal mature brain, only a few astrocytes express low levels of bFGF (2)(3)(4). FGF content increases during the reversible transition of astrocytes from a quiescent to a reactive proliferating state in response to injury or neuronal degeneration.…”

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confidence: 99%

Promoter regions involved in density-dependent regulation of basic fibroblast growth factor gene expression in human astrocytic cells.

Moffett

Kratz

Florkiewicz

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Expression of mitogenic basic fibroblast growth factor (bFGF) in the central nervous system is inhibited by direct cell contact and is implicated in reactive and neoplastic transformation of astrocytes. The molecular mechanisms controlling expression of bFGF were examined in cultures of human astrocytes. Cell-density-dependent depletion of bFGF mRNA levels parallels changes in bFGF protein. Regulation of transcription of a bFGF luciferase reporter gene containing an upstream region (bp -1800 to +314) of the bFGF gene promoter mimicks the density-dependent regulation of the endogenous bFGF gene in transfected astrocytes. Deletion analysis has identified a fragment (bp -650 to -513) and sequences further downstream (bp -274 to +314) as the regions required for the regulation of bFGF gene activity by cell density. Unlike in astrocytes, changing the cell density of glioma cell cultures does not affect the levels ofbFGF protein and mRNA. bFGF luciferase constructs were expressed at the same level in high-or lowdensity cultures of glioma cells, indicating altered regulation of the bFGF gene promoter. Electrophoretic mobility shift assays showed binding of nuclear proteins to a fragment of bFGF gene promoter from bp -650 to -453. This binding was abolished by a deletion of the upstream cell-density-responsive region (bp -650 to -512). Binding was observed with nuclear extracts from subconfluent astrocytes but was reduced in extracts from confluent astrocytes. Our results indicate that induction of bFGF in astrocytes upon reduction of cell density is mediated transcriptionally by positive trans-acting factors interacting with bFGF promoter. In contrast, nuclear proteins from glioma cells bind to the promoter region from bp -650 to -453 independent of cell density. Thus, the constitutive binding of trans-acting factor(s) to the region of the bFGF promoter from bp -650 to -453 may be responsible for the continuous expression of bFGF that leads to the uncontrolled growth of glioma cells.

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Localization of basic fibroblast growth factor and its mRNA after CNS injury

Cited by 202 publications

References 35 publications

Astrogliosis in the Neonatal and Adult Murine Brain Post-Trauma: Elevation of Inflammatory Cytokines and the Lack of Requirement for Endogenous Interferon-γ

Astrogliosis in the Neonatal and Adult Murine Brain Post-Trauma: Elevation of Inflammatory Cytokines and the Lack of Requirement for Endogenous Interferon-γ

Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells

Promoter regions involved in density-dependent regulation of basic fibroblast growth factor gene expression in human astrocytic cells.

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