Molecular Cloning and Expression of Biologically Active Human Glia Maturation Factor‐β

Kaplan, R.; Zaheer, Asgar; Jaye, Michael; Lim, Ramón

doi:10.1111/j.1471-4159.1991.tb03777.x

Cited by 93 publications

(59 citation statements)

References 43 publications

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“…Glia maturation factor (GMF), a 17 kDa highly conserved protein, with 99% homology between humans and rodents, was isolated, sequenced and cloned in our laboratory (Kaplan et al, 1991;Lim et al, 1989;Zaheer et al, 1993). The GMF gene is localized to the long arm of human chromosome 14 (Lander et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3β and caspase-3

et al. 2008

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In the present study we report that a replication-defective adenovirus construct of GMF cDNA (GMF-V) induced overexpression of GMF protein in neuroblastoma (N18) cells caused cytotoxicity and loss of cell viability. A significant increase in activation of GSK-3β occurred after infection with GMF-V when compared with mock and lacZ controls. Overexpression of GMF also increased caspase-3 activity, an early marker of apoptosis. Depletion of GMF gene by introducing GMFspecific siRNA (GsiRNA) completely blocked both activation of GSK-3β and caspase-3 activation whereas a control scrambled siRNA (CsiRNA) had no effect. A cell-permeable peptide inhibitor of GSK-3β, and lithium completely prevented GMF-dependent activation of caspase-3. These results demonstrate that GSK-3 mediates activation of the death domain caspase by GMF overexpression. We also show that the phosphorylation of GSK-3-dependent site of Tau was a consequence of GMFoverexpression in N18 cells. Taken together our results imply that GMF is involved in the signaling leading to the activation of GSK-3β and caspase-3 in N18 cells and strongly suggest its involvement in neurodegeneration since, GSK-3β is known to hyperphosphorylate tau which is associated with the neurotoxicity of neurofibrillary tangles in Alzheimer's disease. KeywordsGlia maturation factor (GMF); neuroblastoma (N18) cells; glycogen synthase kinase-3β (GSK-3β);

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Section: Discussionmentioning

confidence: 99%

“…The Glia Maturation Factor (GMF), a highly conserved brain-specific protein, was isolated, sequenced and cloned in our laboratory (Kaplan et al, 1991;Lim et al, 1989;Lim et al, 1990;Zaheer et al, 1993;Zaheer et al, 1995a;Zaheer et al, 1995b). The functional property of GMF was largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3β and caspase-3

et al. 2008

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“…Recent studies on glia maturation factor (GMF), a brain-specific protein, isolated, sequenced and cloned in our laboratory (Kaplan et al, 1991;Lim et al, 1989;Lim et al, 1990), have given new insights into its role in immunomodulatory and proinflammatory functions in CNS (Lim and Zaheer, 1996;Lim et al, 2000;Zaheer et al, 2002;Zaheer et al, 2004;Zaheer et al, 2006;Zaheer et al, 2007). We have established that overexpression of GMF in astrocytes leads to immune activation of microglia, through secretion of granulocyte-macrophage-colony stimulating factor (GM-CSF), and resulting in production of several pro inflammatory mediators that destroy oligodendrocytes, the myelin forming cells in CNS.…”

Section: Introductionmentioning

confidence: 99%

Diminished cytokine and chemokine expression in the central nervous system of GMF-deficient mice with experimental autoimmune encephalomyelitis

Zaheer¹,

Sahu

et al. 2007

Brain Research

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Pro-inflammatory cytokines/chemokines are implemented in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model with clinical and pathological similarities to multiple sclerosis. We have previously shown that over-expression of glia maturation factor (GMF) in glial cells cause excessive production and secretion of pro-inflammatory cytokines/chemokines sufficient to destroy the myelin forming oligodendroglial cell in-vitro. In this present investigation, we evaluate the expression of pro-inflammatory mediators in the central nervous system (CNS) of GMF+/+ (wild type) mice and GMF−/− (GMF-knockout) mice at the peak of EAE induced by immunization with MOG 35-55 peptide. GMF+/+ (Wt) mice developed severe EAE with a maximal mean clinical score of 3.6 ±0.5 by day 16 post immunization, whereas GMF-KO mice showed significantly delayed EAE with an average onset on day 26 pi with reduced mean clinical score of 1.3 ±0.3. Three of fifteen Wt mice as compared to none of GMF-KO mice died of EAE. Encephalitogenic cells from Wt mice transferred to recipient GMF-KO mice caused very mild and with low incidence of EAE. We determined the differences in the expression of cytokines, IFN-γ, TNF-α, IL-1 β, IL-6, IL-4, IL-10, and chemokines, MIP-1, MIP-2, IP-10, MCP-1, GM-CSF mRNA by quantitative real time RT-PCR in brain and spinal cord. Our results demonstrate significantly low levels of pro inflammatory cytokines/chemokines in the CNS of GMF-KO mice and increased expression in Wt mice with EAE. Our data suggest that GMF play a critical role in CNS inflammation.

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“…This event apparently thought to be the result of a combined autoimmune response to some of the myelin components (Glynn and Linington 1989;Bernard et al 1997;Steinman and Zamvil 2005;Gold et al 2006). Research efforts in recent years on glia maturation factor (GMF), a highly conserved brain-specific protein, isolated, sequenced and cloned in our laboratory (Lim et al 1989;Lim et al 1990;Kaplan et al 1991;Zaheer et al 1993), have demonstrated an immunomodulatory function for GMF. Recently, it has been established that overexpression of GMF in astrocytes leads to immune activation of microglia through secretion of granulocyte-macrophage-colony stimulating factor (GM-CSF) (Zaheer et al J. Neurochem.…”

Section: Introductionmentioning

confidence: 99%

Diminished degradation of myelin basic protein by anti-sulfatide antibody and interferon-γ in myelin from glia maturation factor-deficient mice

Menon

Haas

et al. 2007

Neuroscience Research

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In this study we show the effect of anti-sulfatide (RmAb) antibodies and inflammatory cytokines, TNF-α and IFN-γ in inducing myelin basic protein (MBP) degradation in myelin isolated from control wild type (WT) and glia maturation factor (GMF)-deficient (GMF-KO) mice. GMF was not detected in isolated myelin from WT and GMF-KO mice although it is present in brains of WT mice. Our results show that calcium dependent neutral protease activity caused significantly elevated degradation of 18.5 and/or 17.5 kDa isoforms of MBP in WT-myelin treated with RmAb or IFN-γ. In contrast, MBP degradation in isolated myelin from GMF-KO mice remained unaffected following treatment with RmAb, IFN-γ, or GM-CSF. Neither the 14 kDa isoform of MBP or proteolipid protein (PLP) showed an elevated degradation compared to controls. A virtual absence of GM-CSF, TNF-α and IFN-γ in GMF-KO brain compared to WT was also evident when the animals were challenged with MOG 35-55. Additionally, the myelin from GMF-KO mice showed difference in distribution of myelin oligodendrocyte glycoprotein (MOG) and β-tubulin in a sucrose density gradient myelinaxolemmal fractions compared to WT. Taken together, our data suggests a role for GMF in the biochemical organization of myelin and thereby its effect on MBP degradation induced by RmAb and IFN-γ.

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Molecular Cloning and Expression of Biologically Active Human Glia Maturation Factor‐β

Cited by 93 publications

References 43 publications

Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3β and caspase-3

Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3β and caspase-3

Diminished cytokine and chemokine expression in the central nervous system of GMF-deficient mice with experimental autoimmune encephalomyelitis

Diminished degradation of myelin basic protein by anti-sulfatide antibody and interferon-γ in myelin from glia maturation factor-deficient mice

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