Abstract
Gelsolin plays an important role in the regulation of amyloid beta-protein fibrillogenesis. We report here that calcium ionophore A23187 induces the expression of cytoplasmic gelsolin (c-gelsolin), and that protein kinase C (PKC) is involved in the up-regulation of c-gelsolin. In the presence of calcium, both SH-SY5Y and HEK-293 cells upon treatment with A23187 showed an increase in c-gelsolin expression in a concentration-dependent manner. Calcium-mediated up-regulation of c-gelsolin was inhibited by cycloheximide (a general inhibitor of protein synthesis). When cells were pretreated with staurosporine (an inhibitor of a variety of protein kinases including PKC), the up-regulation of c-gelsolin induced by A23187 was inhibited. Calphostin C, an inhibitor of PKC, blocked the up-regulation of c-gelsolin induced by A23187, while inhibitors of mitogen-activated protein kinases had no effect on c-gelsolin expression. In addition, phorbol-12-myristate-13-acetate, an activator of PKC, up-regulated c-gelsolin expression. These results suggest that calcium mediates up-regulation of c-gelsolin in a PKC-dependent manner.
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Abbreviations
- Aβ:
-
Amyloid beta-protein
- AD:
-
Alzheimer’s disease
- APP:
-
β-amyloid precursor protein
- CHX:
-
Cycloheximide
- DAG:
-
Diacylglycerol
- DMEM:
-
Dulbecco’s Modified Eagle’s Medium
- DMSO:
-
Dimethylsulfoxide
- ERK:
-
Extracellular signal-regulated kinase
- IP3 :
-
Inositol 1,4,5-trisphosphate
- JNK:
-
c-Jun N-terminal kinase
- MAPKs:
-
Mitogen-activated protein kinases
- PKC:
-
Protein kinase C
- PLA2 :
-
Phospholipase A2
- PLC:
-
Phospholipase C
- PMA:
-
Phorbol-12-myristate-13-acetate
References
Yin HL, Kwiatkowski DJ, Mole JE et al (1984) Structure and biosynthesis of cytoplasmic and secreted variants of gelsolin. J Biol Chem 259:5271–5276
Wen D, Corina K, Chow EP et al (1996) The plasma and cytoplasmic forms of human gelsolin differ in disulfide structure. Biochemistry 35:9700–9709
Witke W, Sharpe AH, Hartwig JH et al (1995) Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin. Cell 81:41–51
Endres M, Fink K, Zhu J et al (1999) Neuroprotective effects of gelsolin during murine stroke. J Clin Invest 103:347–354
Yildirim F, Gertz K, Kronenberg G et al (2008) Inhibition of histone deacetylation protects wildtype but not gelsolin-deficient mice from ischemic brain injury. Exp Neurol 210:531–542
Asch HL, Head K, Dong Y et al (1996) Widespread loss of gelsolin in breast cancers of humans, mice, and rats. Cancer Res 56:4841–4845
Prasad SC, Thraves PJ, Dritschilo A et al (1997) Protein expression changes associated with radiation-induced neoplastic progression of human prostate epithelial cells. Electrophoresis 18:629–637
Dosaka-Akita H, Hommura F, Fujita H et al (1998) Frequent loss of gelsolin expression in non-small cell lung cancers of heavy smokers. Cancer Res 58:322–327
Maury CP, Sletten K, Totty N et al (1997) Identification of the circulating amyloid precursor and other gelsolin metabolites in patients with G654A mutation in the gelsolin gene (Finnish familial amyloidosis): pathogenetic and diagnostic implications. Lab Invest 77:299–304
Chauhan VP, Ray I, Chauhan A et al (1999) Binding of gelsolin, a secretory protein, to amyloid beta-protein. Biochem Biophys Res Commun 258:241–246
Hirko AC, Meyer EM, King MA et al (2007) Peripheral transgene expression of plasma gelsolin reduces amyloid in transgenic mouse models of Alzheimer’s disease. Mol Ther 15:1623–1629
Ji L, Chauhan A, Chauhan V (2008) Cytoplasmic gelsolin in pheochromocytoma-12 cells forms a complex with amyloid beta-protein. Neuroreport 19:463–466
Ji L, Chauhan A, Chauhan V (2009) Role of gelsolin in Alzheimer’s disease. In: Sun M-K (ed) Research progress in Alzheimer’s disease and dementia, vol. 4. Nova Science Publishers, Inc., New York, pp 199–218
Ray I, Chauhan A, Wegiel J et al (2000) Gelsolin inhibits the fibrillization of amyloid beta-protein, and also defibrillizes its preformed fibrils. Brain Res 853:344–351
Glenner GG (1983) Alzheimer’s disease. The commonest form of amyloidosis. Arch Pathol Lab Med 107:281–282
Tanaka J, Sobue K (1994) Localization and characterization of gelsolin in nervous tissues: gelsolin is specifically enriched in myelin-forming cells. J Neurosci 14:1038–1052
Matsuoka Y, Saito M, LaFrancois J et al (2003) Novel therapeutic approach for the treatment of Alzheimer’s disease by peripheral administration of agents with an affinity to beta-amyloid. J Neurosci 23:29–33
Antequera D, Vargas T, Ugalde C et al (2009) Cytoplasmic gelsolin increases mitochondrial activity and reduces Abeta burden in a mouse model of Alzheimer’s disease. Neurobiol Dis 36:42–50
Azuma T, Koths K, Flanagan L et al (2000) Gelsolin in complex with phosphatidylinositol 4,5-bisphosphate inhibits caspase-3 and -9 to retard apoptotic progression. J Biol Chem 275:3761–3766
Koya RC, Fujita H, Shimizu S et al (2000) Gelsolin inhibits apoptosis by blocking mitochondrial membrane potential loss and cytochrome c release. J Biol Chem 275:15343–15349
Kusano H, Shimizu S, Koya RC et al (2000) Human gelsolin prevents apoptosis by inhibiting apoptotic mitochondrial changes via closing VDAC. Oncogene 19:4807–4814
Obrig TG, Culp WJ, McKeehan WL et al (1971) The mechanism by which cycloheximide and related glutarimide antibiotics inhibit peptide synthesis on reticulocyte ribosomes. J Biol Chem 246:174–181
Toledo LM, Lydon NB (1997) Structures of staurosporine bound to CDK2 and Capk—new tools for structure-based design of protein kinase inhibitors. Structure 5:1551–1556
Ohori M, Kinoshita T, Okubo M et al (2005) Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex. Biochem Biophys Res Commun 336:357–363
Deng R, Li W, Guan Z et al (2006) Acetylcholinesterase expression mediated by c-Jun-NH2-terminal kinase pathway during anticancer drug-induced apoptosis. Oncogene 25:7070–7077
Su JH, Zhao M, Anderson AJ et al (2001) Activated caspase-3 expression in Alzheimer’s and aged control brain: correlation with Alzheimer pathology. Brain Res 898:350–357
LeBlanc A, Liu H, Goodyer C et al (1999) Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer’s disease. J Biol Chem 274:23426–23436
Rohn TT, Rissman RA, Davis MC et al (2002) Caspase-9 activation and caspase cleavage of tau in the Alzheimer’s disease brain. Neurobiol Dis 11:341–354
Rissman RA, Poon WW, Blurton-Jones M et al (2004) Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 114:121–130
Mouser PE, Head E, Ha KH et al (2006) Caspase-mediated cleavage of glial fibrillary acidic protein within degenerating astrocytes of the Alzheimer’s disease brain. Am J Pathol 168:936–946
Rohn TT, Head E, Su JH et al (2001) Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer’s disease. Am J Pathol 158:189–198
Chauhan V, Chauhan A (2006) Oxidative stress in Alzheimer’s disease. Pathophysiology 13:195–208
Chauhan V, Ji L, Chauhan A (2008) Anti-amyloidogenic, anti-oxidant and anti-apoptotic role of gelsolin in Alzheimer’s disease. Biogerontology 9:381–389
Granados MP, Salido GM, Gonzalez A et al (2006) Dose-dependent effect of hydrogen peroxide on calcium mobilization in mouse pancreatic acinar cells. Biochem Cell Biol 84:39–48
Korzets A, Chagnac A, Weinstein T et al (1999) H2O2 induces DNA repair in mononuclear cells: evidence for association with cytosolic Ca2+ fluxes. J Lab Clin Med 133:362–369
Giambelluca MS, Gende OA (2008) Hydrogen peroxide activates calcium influx in human neutrophils. Mol Cell Biochem 309:151–156
Sharma AK, Rohrer B (2004) Calcium-induced calpain mediates apoptosis via caspase-3 in a mouse photoreceptor cell line. J Biol Chem 279:35564–35572
Gordeeva AV, Zvyagilskaya RA, Labas YA (2003) Cross-talk between reactive oxygen species and calcium in living cells. Biochemistry (Mosc) 68:1077–1080
Maruyama J, Naguro I, Takeda K et al (2009) Stress-activated MAP kinase cascades in cellular senescence. Curr Med Chem 16:1229–1235
Kim J, Wong PK (2009) Oxidative stress is linked to ERK1/2-p16 signaling-mediated growth defect in ATM-deficient astrocytes. J Biol Chem 284:14396–14404
Liscovitch M, Cantley LC (1994) Lipid second messengers. Cell 77:329–334
Berridge MJ (1993) Inositol trisphosphate and calcium signalling. Nature 361:315–325
Cressman CM, Mohan PS, Nixon RA et al (1995) Proteolysis of protein kinase C: mM and microM calcium-requiring calpains have different abilities to generate, and degrade the free catalytic subunit, protein kinase M. FEBS Lett 367:223–227
Demuro A, Mina E, Kayed R et al (2005) Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 280:17294–17300
Chauhan A, Chauhan VP, Brockerhoff H et al (1991) Action of amyloid beta-protein on protein kinase C activity. Life Sci 49:1555–1562
Petersen RC, Smith GE, Ivnik RJ et al (1994) Memory function in very early Alzheimer’s disease. Neurology 44:867–872
Bank B, DeWeer A, Kuzirian AM et al (1988) Classical conditioning induces long-term translocation of protein kinase C in rabbit hippocampal CA1 cells. Proc Natl Acad Sci USA 85:1988–1992
Olds JL, Alkon DL (1993) Protein kinase C: a nexus in the biochemical events that underlie associative learning. Acta Neurobiol Exp (Wars) 53:197–207
Pascale A, Govoni S, Battaini F (1998) Age-related alteration of PKC, a key enzyme in memory processes: physiological and pathological examples. Mol Neurobiol 16:49–62
Cole G, Dobkins KR, Hansen LA et al (1988) Decreased levels of protein kinase C in Alzheimer brain. Brain Res 452:165–174
Govoni S, Bergamaschi S, Racchi M et al (1993) Cytosol protein kinase C downregulation in fibroblasts from Alzheimer’s disease patients. Neurology 43:2581–2586
Wang HY, Pisano MR, Friedman E (1994) Attenuated protein kinase C activity and translocation in Alzheimer’s disease brain. Neurobiol Aging 15:293–298
Kurumatani T, Fastbom J, Bonkale WL et al (1998) Loss of inositol 1,4,5-trisphosphate receptor sites and decreased PKC levels correlate with staging of Alzheimer’s disease neurofibrillary pathology. Brain Res 796:209–221
Desdouits F, Buxbaum JD, Desdouits-Magnen J et al (1996) Amyloid alpha peptide formation in cell-free preparations. Regulation by protein kinase C, calmodulin, and calcineurin. J Biol Chem 271:24670–24674
Favit A, Grimaldi M, Nelson TJ et al (1998) Alzheimer’s-specific effects of soluble beta-amyloid on protein kinase C-alpha and -gamma degradation in human fibroblasts. Proc Natl Acad Sci USA 95:5562–5567
Pakaski M, Balaspiri L, Checler F et al (2002) Human amyloid-beta causes changes in the levels of endothelial protein kinase C and its alpha isoform in vitro. Neurochem Int 41:409–414
Acknowledgments
This work was supported in part by funds from the New York State Office of Mental Retardation and Developmental Disabilities, and by NIH Grant No. AG020992.
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Ji, L., Chauhan, A. & Chauhan, V. Calcium Induces Expression of Cytoplasmic Gelsolin in SH-SY5Y and HEK-293 Cells. Neurochem Res 35, 1075–1082 (2010). https://doi.org/10.1007/s11064-010-0157-8
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DOI: https://doi.org/10.1007/s11064-010-0157-8