Transport of Exogenous Growth Factors and Cytokines to the Cytosol and to the Nucleus

Olsnes, Sjur; Klingenberg, Olav; Wiedlocha, Antoni G

doi:10.1152/physrev.00021.2002

Cited by 106 publications

(100 citation statements)

References 233 publications

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“…However, action and behavior of FGF-1 may not be those of typical cytokines that are secreted and react with target cells by inducing intracellular signals. It does not have a signal peptide, synthesized and located in cytosol (36), so that its release from cells is mediated by an unknown mechanism (37). It has a nuclear translocational sequence, and deletion of this domain results in loss of stimulation of DNA synthesis but not induction of signals (38).…”

Section: Resultsmentioning

confidence: 99%

FGF-1 induces expression of LXRα and production of 25-hydroxycholesterol to upregulate the apoE gene in rat astrocytes

Ito

Iwamoto

et al. 2009

Journal of Lipid Research

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Fibroblast growth factor 1 (FGF-1) enhances apolipoprotein E (apoE) expression and apoE-HDL biogenesis in autocrine fashion in astrocytes (Ito, J., Y. Nagayasu, R. Lu, A. Kheirollah, M. Hayashi, and S. Yokoyama. Astrocytes produce and secrete FGF-1, which promotes the production of apoE-HDL in a manner of autocrine action. J. Lipid Res. 2005. 46: 679-686) associated with healing of brain injury (Tada,T., J-i. Ito, M. Asai, and S. Yokoyama. Fibroblast growth factor 1 is produced prior to apolipoprotein E in the astrocytes after cryo-injury of mouse brain. Neurochem. Int. 2004. 45: 23-30). FGF-1 stimulates mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) to increase cholesterol biosynthesis and phosphatidylinositol 3-OH kinase (PI3K)/Akt to enhance apoE-HDL secretion (Ito, J., Y. Nagayasu, K. Okumura-Noji, R. Lu, T. Nishida, Y. Miura, K. Asai, A. Kheirollah, S. Nakaya, and S. Yokoyama. Mechanism for FGF-1 to regulate biogenesis of apoE-HDL in astrocytes. J. Lipid Res. 2007Res. . 48: 2020Res. -2027. We investigated the mechanism for FGF-1 to upregulate apoE transcription. FGF-1 increased apoE and liver X receptor a (LXRa) mRNAs in rat astrocytes. Increase of LXRa mRNA was suppressed by inhibition of the FGF-1 receptor-1 and MEK/ERK but not by inhibition of PI3K/Akt. The increases of apoE mRNA and apoE-HDL secretion were both inhibited by downregulation or inhibition of LXRa, while they were partially suppressed by inhibiting cholesterol biosynthesis. We identified the liver X receptor element responsible for activation of the rat apoE promoter by FGF-1 located between 2450 and 2320 bp, and the direct repeat 4 (DR4) element in this region (2448 to 2433 bp) was responsible for the activation. Chromatin immunoprecipitation analysis supported that FGF-1 enhanced association of LXR with the rat apoE promoter. FGF-1 partially activated the apoE promoter even in the presence of an MEK inhibitor that inhibits the FGF-1-mediated enhancement of cholesterol biosynthesis. On the other hand, FGF-1 induced production of 25-hydroxycholesterol by MEK/ ERK as an sterol regulatory element-dependent reaction besides cholesterol biosynthesis. We concluded that FGF-1-induced apoE expression in astrocytes depends on LXRa being mediated by both LXRa expression and an LXRa ligand biosynthesis. Apolipoprotein E (apoE) is a glycoprotein composed of 299 amino acids and plays critical roles in lipid metabolism. While most of apolipoproteins are synthesized and secreted primarily by the liver and intestine, apoE is in addition secreted by other cells outside the enterohepatic axis, such as macrophages and adipocytes (1, 2). ApoE is also synthesized by astrocytes and microglia in the central nervous system (CNS) and forms HDL as a major lipoprotein in CNS (3, 4). CNS is segregated from systemic circulation by the blood brain barrier and prevented from access to plasma lipoproteins, so that HDL generated in CNS is the exclusive lipid transport system among the CNS cells (5). ApoE-HDL plays many...

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Section: Resultsmentioning

confidence: 99%

FGF-1 induces expression of LXRα and production of 25-hydroxycholesterol to upregulate the apoE gene in rat astrocytes

Ito

Iwamoto

et al. 2009

Journal of Lipid Research

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“…The nuclear location of FGFR-3-IIIc suggests FGF-2 could carry out its functions via a nuclear route instead of the typical membrane tyrosine receptor kinase cascade pathway. Actually, nuclear translocation of FGFR-1, FGFR-3, and FGFR-4 have previously been reported in several other tissues (Klingenberg et al, 2000;Zammit et al, 2001;Olsnes et al, 2003). Different types of nuclear FGFRs could interact directly with nuclear receptors to execute selectivity of gene activation and achieve different biological functions (Peng et al, 2002;Johnson et al, 2004;Reilly et al, 2004).…”

Section: Fgf-2's Signaling Mechanismmentioning

confidence: 91%

Survival, synaptogenesis, and regeneration of adult mouse spiral ganglion neurons in vitro

Wei

Jin

Järlebark

et al. 2006

Developmental Neurobiology

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ABSTRACT:The inner ear spiral ganglion is populated by bipolar neurons connecting the peripheral sensory receptors, the hair cells, with central neurons in auditory brain stem nuclei. Hearing impairment is often a consequence of hair cell death, e.g., from acoustic trauma. When deprived of their peripheral targets, the spiral ganglion neurons (SGNs) progressively degenerate. For effective clinical treatment using cochlear prostheses, it is essential to maintain the SGN population. To investigate their survival dependence, synaptogenesis, and regenerative capacity, adult mouse SGNs were separated from hair cells and studied in vitro in the presence of various neurotrophins and growth factors. Coadministration of fibroblast growth factor 2 (FGF-2) and glial cell line-derived neurotrophic factor (GDNF) provided support for long-term survival, while FGF-2 alone could strongly promote neurite regeneration.Fibroblast growth factor receptor FGFR-3-IIIc was found to upregulate and translocate to the nucleus in surviving SGNs. Surviving SGNs formed contacts with other SGNs after they were deprived of the signals from the hair cells. In coculture experiments, neurites extending from SGNs projected toward hair cells. Interestingly, adult mouse spiral ganglion cells could carry out both symmetric and asymmetric cell division and give rise to new neurons. The authors propose that a combination of FGF-2 and GDNF could be an efficient route for clinical intervention of secondary degeneration of SGNs. The authors also demonstrate that the adult mammalian inner ear retains progenitor cells, which could commit neurogenesis. '

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“…A route to the cytosol has been established for several proteins that enter cells by receptor-mediated endocytosis, most notably diphtheria toxin, and also anthrax toxin, Clostridium botulinum C2 toxin, tetanus and botulinum neurotoxins (44,45), and several growth factors (46,47). For all these proteins, transfer to the cytosol requires transport to acidic late endosomes-lysosomes.…”

Section: Different Intracellular Routes For Aggregated and Disaggregamentioning

confidence: 99%

Multiple Intracellular Routes in the Cross-Presentation of a Soluble Protein by Murine Dendritic Cells

Palliser

Guillen

et al. 2005

The Journal of Immunology

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Soluble heat shock fusion proteins (Hsfp) stimulate mice to produce CD8+ CTL, indicating that these proteins are cross-presented by dendritic cells (DC) to naive CD8 T cells. We report that cross-presentation of these proteins depends upon their binding to DC receptors, likely belonging to the scavenger receptor superfamily. Hsfp entered DC by receptor-mediated endocytosis that was either inhibitable by cytochalasin D or not inhibitable, depending upon aggregation state and time. Most endocytosed Hsfp was transported to lysosomes, but not the small cross-presented fraction that exited early from the endocytic pathway and required access to proteasomes and TAP. Naive CD8 T cell (2C and OT-I) responses to DC incubated with Hsfp at 1 μM were matched by incubating DC with cognate octapeptides at 1–10 pM, indicating that display of very few class I MHC-peptide complexes per DC can be sufficient for cross-presentation. With an Hsfp (heat shock protein-OVA) having peptide sequences for both CD4+ (OT-II) and CD8+ (OT-I) cells, the CD4 cells responded far more vigorously than the CD8 cells and many more class II MHC-peptide than class I MHC-peptide complexes were displayed.

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Transport of Exogenous Growth Factors and Cytokines to the Cytosol and to the Nucleus

Cited by 106 publications

References 233 publications

FGF-1 induces expression of LXRα and production of 25-hydroxycholesterol to upregulate the apoE gene in rat astrocytes

FGF-1 induces expression of LXRα and production of 25-hydroxycholesterol to upregulate the apoE gene in rat astrocytes

Survival, synaptogenesis, and regeneration of adult mouse spiral ganglion neurons in vitro

Multiple Intracellular Routes in the Cross-Presentation of a Soluble Protein by Murine Dendritic Cells

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