共查询到20条相似文献,搜索用时 46 毫秒
1.
The effects of WR-1065 (2-((aminopropyl)amino)ethanethiol) on cell cycle progression, topoisomerase (topo) IIα activity, and topo IIα phosphorylation in Chinese hamster ovary (CHO) cells have been investigated. Exposure of CHO cells to 0.4 μ m of WR-1065 for 30 min did not effect cell cycle progression nor topo IIα activity and phosphorylation status. However, concentrations ranging from 4 μ m to 4 m m were equally effective in significantly altering these three end points. Cell cycle progression was analysed by flow cytometry. Following a 30 min exposure to this range of concentrations, cells redistributed throughout the cell cycle with the most prominent changes being an accumulation of cells in G2 . Topo IIα activity was measured using a kinetoplast DNA (kDNA) decatenation assay. Enzyme activity was reduced by 50% relative to control levels throughout the 4 μ m to 4 m m dose range tested. Likewise, topo IIα phosphorylation levels, analysed using an immunoprecipitation assay and an antibody specific to the 170 kDa band of topo II, decreased between 42% to 48% of control levels. Inhibition of topo IIα activity in cells exposed to WR-1065 is consistent with the associated observation of WR-1065 mediated cell cycle progression delay and build-up of cells in the G2 phase of the cell cycle. 相似文献
2.
Different Modulation of Protein Kinase C Isozymes in Dibutyryl Cyclic AMP-Differentiated PC12h Cells
Yukiko Uehara-Kunugi Shun Shimohama Hitoshi Kobayakawa Hitomi Tamura Takashi Taniguchi 《Journal of neurochemistry》1994,63(1):125-132
Abstract: PC12h cells can be differentiated into sympathetic neuron-like cells by various agents, including nerve growth factor, basic fibroblast growth factor, cyclic AMP analogues, and protein kinase C (PKC) activators. To study the involvement of PKC in the process of PC12h cell differentiation by cyclic AMP treatment, PKC isozymes (α, βI, βII, and γ) were analyzed using column chromatography and immunoblotting. Two PKC isozymes, PKC(α) and PKC(βII), were predominantly detected in PC12h cells. When stimulated by dibutyryl cyclic AMP, PKC(α) levels declined in the cytosolic fraction of the cells, whereas PKC(βII) levels increased. Increased PKC(βII) levels were also detected in the particulate fraction, whereas particulate PKC(α) levels did not change. The total PKC activity decreased in the cytosolic fraction following cyclic AMP stimulation of PC12h cells, whereas it stayed constant in the particulate fraction. Fractionation on a hydroxyapatite column showed a decreased level of PKC(α) activity and a transient increase followed by a decreased level of PKC(βII) activity. This discrepancy between increased PKC(βII) immunoreactivity and reduced PKC(βII) activity suggested the presence of nonactivatable PKC(βII) in cyclic AMP-treated PC12h extract. These findings indicate that PKC(α) and PKC(βII) are differentially regulated during the differentiation of PC12h cells. In addition, the differentiation of PC12h cells triggered by cyclic AMP seems to involve characteristic alterations of PKC isozymes. 相似文献
3.
Abstract The cell cycle responses of two exponentially growing subpopulations of cells (clones A and D), originally obtained from a human colon adenocarcinoma to X-irradiation, were studied using centrifugal elutriation. Cell suspensions were separated by changing counter-current flow rate while keeping the rotor speed constant (1600 rpm) and the composition of eluted fractions was determined using flow cytometry. The X-ray sensitivity of unseparated clone D cells was somewhat greater than that of clone A cells (e.g. 10% greater at the 10% level of survival). This difference appeared to be due to a greater value of the α parameter (one-hit cell killing), using the linear-quadratic equation in which the relative survival S / S 0 = exp – (αD +βD2 ) with dose (D) in Gy. This finding was confirmed in the cell cycle studies where the α parameter was always greater for the clone D cells than for the clone A cells. The β parameter was essentially the same for both cell lines through the cell cycle. 相似文献
4.
Tachida Y Nakagawa K Saito T Saido TC Honda T Saito Y Murayama S Endo T Sakaguchi G Kato A Kitazume S Hashimoto Y 《Journal of neurochemistry》2008,104(5):1387-1393
The proinflammatory cytokine interleukin (IL)-1β is up-regulated in microglial cells surrounding amyloid plaques, leading to the hypothesis that IL-1β is a risk factor for Alzheimer's disease. However, we unexpectedly found that IL-1β significantly enhanced α-cleavage, indicated by increases in sAPPα and C83, but reduced β-cleavage, indicated by decreases in sAPPβ and Aβ40/42, in human neuroblastoma SK-N-SH cells. IL-1β did not significantly alter the mRNA levels of BACE1, ADAM-9, and ADAM-10, but up-regulated that of TACE by threefold. The proform and mature form of TACE protein were also significantly up-regulated. A TACE inhibitor (TAPI-2) concomitantly reversed the IL-1β-dependent increase in sAPPα and decrease in sAPPβ, suggesting that APP consumption in the α-cleavage pathway reduced its consumption in the β-cleavage pathway. IL-1Ra, a physiological antagonist for the IL-1 receptor, reversed the effects of IL-1β, suggesting that the IL-1β-dependent up-regulation of α-cleavage is mediated by the IL-1 receptor. IL-1β also induced this concomitant increase in α-cleavage and decrease in β-cleavage in mouse primary cultured neurons. Taken together we conclude that IL-1β is an anti-amyloidogenic factor, and that enhancement of its signaling or inhibition of IL-1Ra activity could represent potential therapeutic strategies against Alzheimer's disease. 相似文献
5.
Using human endothelial cells, we define a mechanism that accounts for the induction of interleukin 8 (IL-8) by protein I/IIf, an adhesin from Streptococcus mutans serotype f. We report that protein I/IIf interactions with endothelial cells increased the tyrosine phosphorylation of three cellular components with relative mass of 145 000, 125 000 and 70 000 in endothelial cells. These proteins were identified as phospholipase Cγ (PLCγ), focal adhesion kinase (FAK) and paxillin after immunoprecipitation with monoclonal antibodies (mAbs) and immunoblotting with antiphosphotyrosine mAbs. These results suggested that β1 integrins could be one of the components implicated in the modulin activity of protein I/IIf. By incubating protein I/IIf with either purified α5β1 integrins or with α5β1 integrins overexpressing CHO cells, we demonstrated that α5β1 integrins act as cell receptors for protein I/IIf. We also showed that protein I/IIf interactions with α5β1 integrins lead to IL-8 secretion. Using specific inhibitors, we demonstrated that protein I/IIf-induced IL-8 release involves mitogen-activated protein kinases (MAPKs), and that PLCγ and PKC also seem to contribute to protein I/IIf stimulation. However, PI-3K activation is not involved in IL-8 release. Altogether, these results indicate that, after binding to α5β1 integrins, protein I/IIf induces IL-8 release by activating the MAPKs signalling pathways. 相似文献
6.
Timothy Joseph-home Nigel J. Manning Derek Hollomon Steven L. Kelly 《FEMS microbiology letters》1995,127(1-2):29-34
Abstract Resistance to azole antifungals in Ustilago maydis was associated with a leaky defect in sterol Δ 5(6) desaturase. This defect resulted in reduced accumulation of 14α-methylergosta-24(28)-diene-3β, 6 α-diol and an increase in the proportion of 14α-methylfecosterol in treated cells when compared to the parent strain. The results demonstrate the importance of this mechanism in pathogenic fungi. 相似文献
7.
8.
Hiromichi Kawai Hitoshi Yasuda Masahiko Terada Mariko Omatsu-Kanbe Ryuichi Kikkawa 《Journal of neurochemistry》1997,69(1):330-339
Abstract: Three isoforms of catalytic α subunits and two isoforms of β subunits of Na+ ,K+ -ATPase were detected in rat sciatic nerves by western blotting. Unlike the enzyme in brain, sciatic nerve Na+ ,K+ -ATPase was highly resistant to ouabain. The ouabain-resistant α1 isoform was demonstrated to be the predominant form in rat intact sciatic nerve by quantitative densitometric analysis and is mainly responsible for sciatic nerve Na+ ,K+ -ATPase activity. After sciatic nerve injury, the α3 and β1 isoforms completely disappeared from the distal segment owing to Wallerian degeneration. In contrast, α2 and β2 isoform expression and Na+ ,K+ -ATPase activity sensitive to pyrithiamine (a specific inhibitor of the α2 isoform) were markedly increased in Schwann cells in the distal segment of the injured sciatic nerve. These latter levels returned to baseline with nerve regeneration. Our results suggest that α3 and β1 isoforms are exclusive for the axon and α2 and β2 isoforms are exclusive for the Schwann cell, although axonal contact regulates α2 and β2 isoform expressions. Because the β2 isoform of Na+ ,K+ -ATPase is known as an adhesion molecule on glia (AMOG), increased expression of AMOG/β2 on Schwann cells in the segment distal to sciatic nerve injury suggests that AMOG/β2 may act as an adhesion molecule in peripheral nerve regeneration. 相似文献
9.
10.
Epigenetic activation of α4, β2 and β6 integrins involved in cell migration in trichostatin A-treated Hep3B cells 总被引:4,自引:0,他引:4
Summary The epigenetic modulation by histone deacetylase (HDAC) inhibitors including trichostatin A (TSA) has been known to block
cell proliferation, induce apoptosis and inhibit cell migration in human cancer cells that represents the potential therapeutic
agents for cancers and fibrosis. However, more than 55% of Hep3B cells remained alive after our initial study of 100 nM TSA
treatment. To further study the epigenetic modulation and the biological function of newly activated genes by HDAC inhibitor
involved in HCC progression and metastasis, we profiled 23 integrin genes including 15α and 8β in TSA-treated Hep3B cells.
Six integrins including three down-regulated α6, α10, β8 and three significant up-regulated α4, β2, β6 integrins were revealed
after semi-quantitative RT-PCR. To confirm the epigenetic modulation and explore their biological functions, we selected the
three significantly up-regulated integrins for confirmation of protein up-regulation, hyperacetylated-histones by ChIP assays,
and functional inhibition by specific neutralizing antibodies of integrins. Our results indicated that epigenetic modulation
in TSA-treated Hep3B cells up-regulated new integrins including α4, β2 and β6 and reduced migration activities by specific
neutralizing antibodies to 61.3%, 42.4% and 34.5%, respectively. Our novel findings provided a better understanding of the
epigenetic modulation of integrins and suggested that targeting the epigenetic up-regulated integrins to abrogate the migration
activity might be a promising strategy to prevent HCC progression. 相似文献
11.
Olga Gorbounova Anne-Lie Svensson Patrik Jönsson Malahat Mousavi Hui Miao Eva Hellström-Lindahl Agneta Nordberg 《Journal of neurochemistry》1998,70(3):1134-1142
Abstract: For a study of the underlying mechanisms of a possible interaction between ethanol and nicotinic receptors during ethanol dependence, the aim of this work was to investigate the effect of chronic ethanol exposure on nicotinic receptor subtypes in a transfected fibroblast cell line (M10 cells) stably expressing α4β2 nicotinic receptor subtype and an SH-SY5Y neuroblastoma cell line expressing α3, α5, α7, β2, and β4 nicotinic acetylcholine receptor (nAChR) subunits. A significant dose-related decrease (−30–80%) in number of [3 H]nicotine binding sites was observed in ethanol-treated (25–240 m M ) compared with untreated M10 cells. Similarly, 4-day treatment with ethanol in concentrations relevant to chronic alcoholism (100 m M ) decreased the number of nicotinic receptor binding sites in the SH-SY5Y cells when measured using [3 H]epibatidine. When M10 cells were chronically treated with nicotine, ethanol partly inhibited the up-regulation of nicotinic receptors when present in the cells together with nicotine. Chronic treatment for 4 days with 100 m M ethanol significantly decreased the mRNA level for the α3 nAChR subunit (−39%), while the mRNA levels for the α7 (+30%) and α4 (+22%) subunits were significantly increased. Chronic ethanol treatment did not affect the mRNA levels for the β2 nAChR subunit. Changes in the levels of nAChR protein and mRNA may have adaptive significance and be involved in the development of dependence, tolerance, and addiction to chronic ethanol and nicotine exposure. They also may be targets for therapeutic strategies in the treatment of ethanol and nicotine dependence. 相似文献
12.
Here we show that low-dose cyclophosphamide (CY), that depends for its therapeutic effectiveness on the immunopotentiating
activity of the drug for T cell-mediated tumor-eradicating immunity, is curative for ~80% of wild-type (WT) mice bearing a
large s.c. MOPC-315 tumor, but only for ~10% of IFN-α/βR−/− mice bearing a large s.c. MOPC-315 tumor. Histopathological examination of the s.c. tumors of such mice on day 4 after the
chemotherapy revealed that the low dose of CY led to accumulation of T lymphocytes in both the WT and the IFN-α/βR−/− mice. However, in the CY treated tumor bearing WT mice the T lymphocytes were present throughout the tumor mass and in direct
contact with tumor cells, but in the CY treated tumor bearing IFN-α/βR−/− mice most of the T lymphocytes remained in blood vessels. In addition to being important for CY-induced transendothelial
migration of T lymphocytes into the tumor mass, we show here that signaling via the IFN-α/βR is also important for CY-induced
control of metastatic tumor progression in the spleen and liver of the tumor bearing mice. Finally, CY cured tumor bearing
WT mice were resistant to a subsequent challenge with MOPC-315 tumor cells, but the few CY cured tumor bearing IFN-α/βR−/− mice were not. Thus, signaling via the IFN-α/βR on host cells in MOPC-315 tumor bearers is important for CY-induced: (a)
transendothelial migration of T lymphocytes into the tumor mass and the eradication of the primary tumor, (b) control of metastatic
tumor progression, and (c) resistance to a subsequent tumor challenge.
This work was supported by Research Grant 03-19 from the American Cancer Society-Illinois Division. 相似文献
13.
Cutolo M Capellino S Montagna P Ghiorzo P Sulli A Villaggio B 《Arthritis research & therapy》2005,7(5):R1124-R1132
Sex hormones seem to modulate the immune/inflammatory responses by different mechanisms in female and male rheumatoid arthritis
patients. The effects of 17β-oestradiol and of testosterone were tested on the cultured human monocytic/macrophage cell line
(THP-1) activated with IFN-γ in order to investigate their role in cell proliferation and apoptosis. Activated human THP-1
cells were cultured in the presence of 17β-oestradiol and testosterone (final concentration, 10 nM). The evaluation of markers
of cell proliferation included the NF-κB DNA-binding assay, the NF-κB inhibition complex, the proliferating cell nuclear antigen
expression and the methyl-tetrazolium salt test. Apoptosis was detected by the annexin V-propidium assay and by the cleaved
poly-ADP ribose polymerase expression. Specific methods included flow analysis cytometry scatter analysis, immunocytochemistry
and western blot analysis. Cell growth inhibition and increased apoptosis were observed in testosterone-treated THP-1 cells.
Increased poly-ADP ribose polymerase-cleaved expression and decreased proliferating cell nuclear antigen expression, as well
as an increase of IκB-α and a decrease of the IκB-α phosphorylated form (ser 32), were found in testosterone-treated THP-1
cells. However, the NF-κB DNA binding was found increased in 17β-oestradiol-treated THP-1 cells. The treatment with staurosporine
(enhancer of apoptosis) induced decreased NF-κB DNA binding in all conditions, but particularly in testosterone-treated THP-1
cells. Treatment of THP-1 by sex hormones was found to influence cell proliferation and apoptosis. Androgens were found to
increase the apoptosis, and oestrogens showed a protective trend on cell death – both acting as modulators of the NF-κB complex. 相似文献
14.
Mitsuhiro Niimi Yumiko Yamamoto Hiroshi Takemori †Atsuhiko Uno Yuki Kondo Atsushi Yamatodani 《Journal of neurochemistry》1997,69(2):851-858
Abstract: We investigated the effect of lipopolysaccharide (LPS) and various inflammatory cytokines on the histidine decarboxylase (HDC) activity in cultured cells of the rat embryonic brain. Histaminergic neuronal cell bodies were supposed to exist in cultured cells of the diencephalon but not in those of the cortex. The HDC activity was elevated by adding LPS and interleukin-1 β (IL-1β) but not by tumor necrosis factor-α (TNF-α) and IL-6 to the mixed primary cultures of diencephalon. In the adherent cell fraction of the cultured diencephalon cells, HDC activity was also enhanced by LPS and IL-1β. In a similar manner, LPS augmented HDC activity in the mixed primary culture of cerebral cortical cells and in its adherent cell fraction. The effects of IL-1β but not LPS in the mixed primary culture of diencephalon were canceled by a prior exposure to cytosine-β- d -arabinofuranoside. The changes in HDC activity after exposure to LPS for 12 h were not accompanied by increased mRNA levels. In these cell cultures, mast cells were not detected by Alcian Blue staining. These results indicated the presence of the third type of HDC-bearing cell besides neurons and mast cells in the brain. The increase of HDC activity by IL-1β might be due to cell proliferation. 相似文献
15.
Abstract When a thermophilic bacillus was incubated with progesterone for approx. 18 h at 65°C, four progesterone-based metabolites were produced in moderate quantities. Two products were found to be hydroxy derivatives, i.e. 6α-hydroxyprogesterone and 6β-hydroxyprogesterone and two were C-20 reduced epimers of progesterone, i.e. 20α- and 20β-dihydroprogesterone. 6α-Hydroxyprogesterone is a rare microbial transformation product.
Inhibition of hydroxylation by azole-based fungicides and the presence of a carbon-monoxide-reduced difference-spectrum absorbance maximum at 448 nm in the soluble cell fraction suggest that the hydroxylase(s) might be cytochromes(s) P450. The dihydroprogesterones were probably produced by oxidoreductases. 相似文献
Inhibition of hydroxylation by azole-based fungicides and the presence of a carbon-monoxide-reduced difference-spectrum absorbance maximum at 448 nm in the soluble cell fraction suggest that the hydroxylase(s) might be cytochromes(s) P450. The dihydroprogesterones were probably produced by oxidoreductases. 相似文献
16.
Joshua A. Berman James L. Roberts Dolan B. Pritchett 《Journal of neurochemistry》1994,63(5):1948-1954
Abstract: Levels of mRNA for the major subunits of the GABAA receptor were assayed in the rat pituitary anterior and neurointermediate lobes by ribonuclease protection assay. α1, β1, β2, β3, and γ2s were found to be the predominant subunits in the anterior lobe, whereas α2, α3, β1, β3, γ2s, and γ1 were the predominant subunits expressed in the neurointermediate lobe. α5, α6, and δ subunits were not detectable. Hill and Scatchard analysis of [3 H]muscimol binding to anterior and neurointermediate lobe membranes showed high-affinity binding sites with dissociation constants of 5.6 and 4.5 n M , respectively, and Hill coefficients near 1. Muscimol sites were present at a maximum of 126 fmol/mg in the anterior lobe and 138 fmol/mg in the neurointermediate lobe. The central-type benzodiazepine antagonist [3 H]Ro 15-1788 bound to a high-affinity site with a dissociation constant of 1.5 n M in both tissues, at a maximum of 60 fmol/mg in anterior pituitary and 72 fmol/mg in neurointermediate lobe. A Hill coefficient of 1 was measured for this site in both tissues. Assays of CL 218 872 displacement of Ro 15-1788 were consistent with a pure type I benzodiazepine site in the anterior lobe and a pure type II site in the intermediate lobe. These results are consistent with both tissue-specific expression of particular GABAA receptor subunits and receptor heterogeneity within individual cells in the pituitary. 相似文献
17.
Rie Hosoi Toshio Matsuda Shoichi Asano Hiroaki Nakamura Hitoshi Hashimoto Kazuhiro Takuma Akemichi Baba 《Journal of neurochemistry》1997,69(5):2189-2196
Abstract: There are two α-subunit isoforms (α1 and α2) and two β-subunit isoforms (β1 and β2) of Na+ ,K+ -ATPase in astrocytes, but the functional heterodimer composition is not known. Ouabain (0.5–1.0 m M ) increased the levels of α1 and β1 mRNAs, whereas it decreased those of α2 and β2 mRNAs in cultured rat astrocytes. The increases in α1 and β1 mRNAs were observed at 6–48 h after addition of the inhibitor. Immunochemical analyses showed that ouabain increased α1 and β1, but not α2 and β2, proteins, and that the isoforms in control and ouabain-treated cultures were of glial origin. Low extracellular K+ and monensin (20 µ M ) mimicked the effect of ouabain on α1 mRNA. The ouabain-induced increase in α1 mRNA was blocked by the protein synthesis inhibitor cycloheximide (10 µ M ), the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane- N,N,N',N' -tetraacetic acid tetraacetoxymethyl ester (30 µ M ), and the calcineurin inhibitor FK506 (1 n M ). These findings indicate that chronic inhibition of Na+ ,K+ -ATPase up-regulates the α1 and β1, but not α2 and β2, isoforms in astrocytes, suggesting a functional coupling of α1β1 complex. They also suggest that intracellular Na+ , Ca2+ , and calcineurin may be involved in ouabain-induced up-regulation of the enzyme in astrocytes. 相似文献
18.
β-amyloid peptide 1–42 (Aβ1–42 ) and hyperphosphorylated tau are associated with neurodegeneration in Alzheimer's disease. Emerging evidence indicates that Aβ1–42 can potentiate hyperphosphorylation of tau in cell lines and in transgenic mice, but the underlying mechanism(s) remains unclear. In this study, Aβ1–42 -induced tau phosphorylation was investigated in differentiated PC12 cells. Treatment of cells with Aβ1–42 increased phosphorylation of tau at serine-202 as detected by AT8 antibody. This Aβ1–42 -induced tau phosphorylation paralleled phosphorylation of glycogen synthase kinase-3β (GSK-3β) at tyrosine-216 (GSK-3β-pY216), which was partially inhibited by the GSK-3β inhibitor, CHIR98023. Aβ1–42 -induced tau phosphorylation and increase in GSK-3β-pY216 phosphorylation were also partially attenuated by α7 nicotinic acetylcholine receptor (α7 nAChR) selective ligands including agonist A-582941 and antagonists methyllycaconitine and α-bungarotoxin. The α7 nAChR agonist and the GSK-3β inhibitor had no additive effect. These observations suggest that α7 nAChR modulation can influence Aβ1–42 -induced tau phosphorylation, possibly involving GSK-3β. This study provides evidence of nAChR mechanisms underlying Aβ1–42 toxicity and tau phosphorylation, which, if translated in vivo , could provide additional basis for the utility of α7 nAChR ligands in the treatment of Alzheimer's disease. 相似文献
19.
Abstract— The β-adrenergic agonist, isoproterenol and the α- and β-adrenergic agonist. NA. raise the intracellular concentration of cyclic AMP in cultures of dissociated perinatal mouse brain. This rise is prevented by a β- but not by an α-adrenergic antagonist. The maximal level of cyclic AMP reached in the presence of isoproterenol is markedly higher than that found after exposure to NA. However, if NA is used along with an α-adrenergic antagonist, cyclic AMP levels as high as those after isoproterenol are measured. Agonists with α-adrenergic activity including NA decrease the response to isoproterenol. The decrease is blocked by α-adrenergic antagonists. From this and additional evidence it is concluded: (1) The increase in the level of cyclic AMP caused by β-adrenergic agonists is due to β-receptor-mediated stimulation of adenylate cyclase; (2) the inhibition of this effect by α-adrenergic agonists is mediated by adrenergic α-receptors; (3) the α- and β-adrenergic receptors are likely to be located on the same cells, probably the most abundant putative glial precursor cells. The simultaneous stimulation of α- and β-adrenergic receptors on the same cell may be of significance in the regulation of the response to NA. 相似文献
20.
Katsutoshi Furukawa Bryce L. Sopher †Russell E. Rydel James G. Begley Dao G. Pham George M. Martin †Michael Fox Mark P. Mattson 《Journal of neurochemistry》1996,67(5):1882-1896
Abstract: Proteolytic cleavage of β-amyloid precursor protein (βAPP) by α-secretase results in release of one secreted form (sAPP) of APP (sAPPα), whereas cleavage by β-secretase releases a C-terminally truncated sAPP (sAPPβ) plus amyloid β-peptide (Aβ). βAPP mutations linked to some inherited forms of Alzheimer's disease may alter its processing such that levels of sAPPα are reduced and levels of sAPPβ increased. sAPPαs may play important roles in neuronal plasticity and survival, whereas Aβ can be neurotoxic. sAPPα was ∼100-fold more potent than sAPPβ in protecting hippocampal neurons against excitotoxicity, Aβ toxicity, and glucose deprivation. Whole-cell patch clamp and calcium imaging analyses showed that sAPPβ was less effective than sAPPα in suppressing synaptic activity, activating K+ channels, and attenuating calcium responses to glutamate. Using various truncated sAPPα and sAPPβ APP695 products generated by eukaryotic and prokaryotic expression systems, and synthetic sAPP peptides, the activity of sAPPα was localized to amino acids 591–612 at the C-terminus. Heparinases greatly reduced the actions of sAPPαs, indicating a role for a heparin-binding domain at the C-terminus of sAPPα in receptor activation. These findings indicate that alternative processing of βAPP has profound effects on the bioactivity of the resultant sAPP products and suggest that reduced levels of sAPPα could contribute to neuronal degeneration in Alzhiemer's disease. 相似文献