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1.
Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance 总被引:3,自引:0,他引:3
Balaraman Y Limaye AR Levey AI Srinivasan S 《Cellular and molecular life sciences : CMLS》2006,63(11):1226-1235
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading
cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the
serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in
the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review,
we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor
protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt,
Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD.
Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006 相似文献
2.
Victoria C. Garside Alex C. Chang Aly Karsan Pamela A. Hoodless 《Cellular and molecular life sciences : CMLS》2013,70(16):2899-2917
Congenital heart defects affect approximately 1–5 % of human newborns each year, and of these cardiac defects 20–30 % are due to heart valve abnormalities. Recent literature indicates that the key factors and pathways that regulate valve development are also implicated in congenital heart defects and valve disease. Currently, there are limited options for treatment of valve disease, and therefore having a better understanding of valve development can contribute critical insight into congenital valve defects and disease. There are three major signaling pathways required for early specification and initiation of endothelial-to-mesenchymal transformation (EMT) in the cardiac cushions: BMP, TGF-β, and Notch signaling. BMPs secreted from the myocardium set up the environment for the overlying endocardium to become activated; Notch signaling initiates EMT; and both BMP and TGF-β signaling synergize with Notch to promote the transition of endothelia to mesenchyme and the mesenchymal cell invasiveness. Together, these three essential signaling pathways help form the cardiac cushions and populate them with mesenchyme and, consequently, set off the cascade of events required to develop mature heart valves. Furthermore, integration and cross-talk between these pathways generate highly stratified and delicate valve leaflets and septa of the heart. Here, we discuss BMP, TGF-β, and Notch signaling pathways during mouse cardiac cushion formation and how they together produce a coordinated EMT response in the developing mouse valves. 相似文献
3.
Foser S Redwanz I Ebeling M Heizmann CW Certa U 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2387-2396
A hallmark of resistance to type I interferons (IFNs) is the lack of antiproliferative responses. We show here that costimulation with IFN-alpha and transforming growth factor beta-1 (TGF-beta) potentiates antiproliferative activity in a sensitive (ME15) and resistant (D10) human melanoma cell line. A DNA microarray-based search for proliferation control genes involved that are cooperatively activated by IFN-alpha and TGF-beta, yielded 28 genes. Among these are the insulin-like growth factor-binding protein 3 (IGFBP3) and the calcium-binding protein S100A2; we demonstrate, that recombinant IGFBP3 protein is a potent growth inhibitor requiring TGF-beta activity. The antiproliferative activity of S100A2 is significantly enhanced by IFN-alpha in stably transfected ME15 or D10 cell lines. We show for the first time that IFN-alpha is a potent inducer of intracellular calcium release required for activation of S100A2. Our study provides a functional link between IFN-alpha and TGF-beta signaling and extends the function of IFN signaling to calcium-sensitive processes. 相似文献
4.
Endogenous electrical fields (EFs) at corneal and skin wounds send a powerful signal that directs cell migration during wound
healing. This signal therefore may serve as a fundamental regulator directing cell polarization and migration. Very little
is known of the intracellular and molecular mechanisms that mediate EF-induced cell polarization and migration. Here, we report
that Chinese hamster ovary (CHO) cells show robust directional polarization and migration in a physiological EF (0.3–1 V/cm)
in both dissociated cell culture and monolayer culture. An EF of 0.6 V/cm completely abolished cell migration into wounds
in monolayer culture. An EF of higher strength (≥1 V/cm) is an overriding guidance cue for cell migration. Application of
EF induced quick phosphorylation of glycogen synthase kinase 3β (GSK-3β) which reached a peak as early as 3 min in an EF.
Inhibition of protein kinase C (PKC) significantly reduced EF-induced directedness of cell migration initially (in 1–2 h).
Inhibition of GSK-3β completely abolished EF-induced GA polarization and significantly inhibited the directional cell migration,
but at a later time (2–3 h in an EF). Those results suggest that GSK-3β is essential for physiological EF-induced Golgi apparatus
(GA) polarization and optimal electrotactic cell migration. 相似文献
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Testicular Δ5-3β dehydrogenase,ascorbic acid and dehydroascorbic acid in actinomycin D-treated toads
Summary Unilaterally intratesticular injection of actionomycin D in toad inhibited 5-3 dehydrogenase activity with significant increase of dehydroascorbic acid and decrease of ascorbic acid level in the testis.Acknowledgments. Thanks are due to Prof. C. Deb, Department of Physiology, Calcutta University, for his suggestions and constant encouragment. Thanks are also extended to Mr R.K. Bhattacharya Microphotographer Department of Physiology, for his kind cooperation. 相似文献
7.
Effect of testosterone and 17-β estradiol on limb regeneration in the newt,Notophthalmus viridescens
S. R. Scadding 《Cellular and molecular life sciences : CMLS》1979,35(12):1665-1666
Summary Gonadectomy, or injections of testosterone or 17- estradiol, had no apparent effect on the rate of regeneration or histological appearance of limb regenerates in the newt,Notophthalmus viridescens. Neither promotion, nor inhibition of limb regeneration was observed.This work was supported by a grant from the National Research Council of Canada to S.R.S. 相似文献
8.
In 1986, Brown and Clemmons (Proc. natl Acad. Sci. USA83 (1986) 3321) showed that platelets contain a substance, platelet-derived growth inhibitor (PDGI), that inhibits in vitro endothelial cell replication. Although platelets are rich in transforming grwoth factor (TGF-), PDGI was considered not to be related to TGF-, on the basis of its reported properties (extraction from platelets at neutral pH, binding to heparin-Sepharose). However, we purified PDGI to near homogeneity and showed that on the basis of HPLC retention behavior, in vitro growth inhibitory activities with several cell types, receptor binding, and immunoneutralization of growth inhibitory activity with specific anti-TGF- type 1 antibodies, PDGI is most probably identical with TGF- type 1. 相似文献
9.
Tamara Jefferson Ulrich auf dem Keller Caroline Bellac Verena V. Metz Claudia Broder Jana Hedrich Anke Ohler Wladislaw Maier Viktor Magdolen Erwin Sterchi Judith S. Bond Arumugam Jayakumar Heiko Traupe Athena Chalaris Stefan Rose-John Claus U. Pietrzik Rolf Postina Christopher M. Overall Christoph Becker-Pauly 《Cellular and molecular life sciences : CMLS》2013,70(2):309-333
The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin?/? mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes. 相似文献
10.
K. Arishima S. Nakama Y. Morikawa Y. Hashimoto Y. Eguchi 《Cellular and molecular life sciences : CMLS》1978,34(2):262-263
Summary Radioactivity in the fetal plasma 1 h after maternal injection of14C-4-corticosterone or14C-4-estradiol-17 on day 21 of gestation was markedly higher than that 1 h after injection on day 22. Radioactivity in the maternal plasma was not different on these 2 days. The results suggest that the placental permeability to steroids from the mother to the fetus declines toward the end of gestation in the rat.Acknowledgment. We are indebted to Professor Tatsuo Imori (Department of Veterinary Surgery, College of Agriculture, University of Osaka Prefecture) for his valuable suggestions during the course of this study. 相似文献
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F. Dessì-Fulgheri C. Lupo di Prisco P. Verdarelli 《Cellular and molecular life sciences : CMLS》1976,32(1):114-115
Summary The effect of complete and tactile isolation on plasma testosterone and estradiol-17 was studied in male rats at the age of 60 and 180 days. A decrease in the plasma levels of the two hormones was observed. 相似文献
13.
Galat A 《Cellular and molecular life sciences : CMLS》2011,68(20):3437-3451
The transforming growth factor-β (TGFβ) superfamily of proteins and their receptors are crucial developmental factors for
all metazoan organisms. Cystine-knot (CK) motif is a spatial feature of the TGFβ superfamily of proteins whereas the extra-cellular
domains (ectodomains) of their respective receptors form three-fingered protein domain (TFPD), both stabilized by tight cystine
networks. Analyses of multiple sequence alignments of these two domains encoded in various genomes revealed that the cystines
forming the CK and TFPD folds are conserved, whereas the remaining polypeptide patches are diversified. Orthologues of the
human TGFβs and their respective receptors expressed in diverse vertebrates retain high sequence conservation. Examination
of 3D structures of various TGFβ factors bound to their receptors have revealed that the CK and TFPD domains display several
similar spatial traits suggesting that these two different protein folds might have been acquired from a common ancestor. 相似文献
14.
Iva Hafner-Bratkovi? Mojca Ben?ina Katherine A. Fitzgerald Douglas Golenbock Roman Jerala 《Cellular and molecular life sciences : CMLS》2012,69(24):4215-4228
Prion diseases are fatal transmissible neurodegenerative diseases, characterized by aggregation of the pathological form of prion protein, spongiform degeneration, and neuronal loss, and activation of astrocytes and microglia. Microglia can clear prion plaques, but on the other hand cause neuronal death via release of neurotoxic species. Elevated expression of the proinflammatory cytokine IL-1β has been observed in brains affected by several prion diseases, and IL-1R-deficiency significantly prolonged the onset of the neurodegeneration in mice. We show that microglial cells stimulated by prion protein (PrP) fibrils induced neuronal toxicity. Microglia and macrophages release IL-1β upon stimulation by PrP fibrils, which depends on the NLRP3 inflammasome. Activation of NLRP3 inflammasome by PrP fibrils requires depletion of intracellular K+, and requires phagocytosis of PrP fibrils and consecutive lysosome destabilization. Among the well-defined molecular forms of PrP, the strongest NLRP3 activation was observed by fibrils, followed by aggregates, while neither native monomeric nor oligomeric PrP were able to activate the NLRP3 inflammasome. Our results together with previous studies on IL-1R-deficient mice suggest the IL-1 signaling pathway as the perspective target for the therapy of prion disease. 相似文献
15.
The in vivo expression of the globin genes of theβ cistron in γ-,δ-, andδβ-thalassemia heterozygotes
A. J. Dimovski A. D. Adekile T. H. J. Huisman 《Cellular and molecular life sciences : CMLS》1994,50(2):167-170
There is considerable evidence suggesting that the switch from to and chain production after birth is due, in part, to silencing of the genes by stage-specific factors which bind to their promoters and to the competition from the adult ( and ) genes for a common enhancer element located in the locus control region. As a consequence one can expect that the increased Hb F production in adults with hereditary persistence of fetal hemoglobin or -thalassemia is directed mainly by -globin genes in cis to the deletion(s) responsible for these conditions. Here we review data on heterozygotes with -, -, or -thalassemia, who also had anAT mutation, in cis or in trans, which was used as a marker of gene expression. The results show that a deletion affecting adult genes favors the expression of genes in cis, while the deletion of a single gene does not affect the expression of the gene in cis but leads to a faster switch postnatally. 相似文献
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E. Hubin N. A. J. van Nuland K. Broersen K. Pauwels 《Cellular and molecular life sciences : CMLS》2014,71(18):3507-3521
The aggregation and deposition of the amyloid-β peptide (Aβ) in the brain has been linked with neuronal death, which progresses in the diagnostic and pathological signs of Alzheimer’s disease (AD). The transition of an unstructured monomeric peptide into self-assembled and more structured aggregates is the crucial conversion from what appears to be a harmless polypeptide into a malignant form that causes synaptotoxicity and neuronal cell death. Despite efforts to identify the toxic form of Aβ, the development of effective treatments for AD is still limited by the highly transient and dynamic nature of interconverting forms of Aβ. The variability within the in vivo “pool” of different Aβ peptides is another complicating factor. Here we review the dynamical interplay between various components that influence the heterogeneous Aβ system, from intramolecular Aβ flexibility to intermolecular dynamics between various Aβ alloforms and external factors. The complex dynamics of Aβ contributes to the causative role of Aβ in the pathogenesis of AD. 相似文献
19.
Summary Three cultured human cell lines, renal cancer cells (ACHN), bladder cancer cells (EJ), and fibroblasts transformed in culture by Co-60 gamma rays (KMST-6), when treated with interferon-, produced 1.5 to 4 times as much plasminogen activator as the untreated control cultures. This enhanced production of PA was inhibited by cycloheximide or actinomycin D. 相似文献
20.
The identification of the aspartic protease BACE1 (β-secretase) was a defining event in research aimed at understanding the
molecular mechanisms that underlie Alzheimer’s disease (AD) pathogenesis. This is because BACE1 catalyses the rate limiting
step in the production of amyloid-β (Aβ) the principal component of plaque pathology in AD, the excessive production of which
is believed to be a primary cause of neurodegeneration, and cognitive dysfunction in AD. Subsequent discoveries showed that
genetic deletion of BACE1 completely abolishes Aβ production and deposition in vivo, and that BACE1 activity is significantly increased in AD brain. In this review we present current knowledge on BACE1, discussing
its structure, function and complex regulation with a view to understanding BACE1 function in the brain, and BACE1 as a target
in blocking aberrant Aβ production in AD.
Received 15 May 2008; received after revision 13 June 2008; accepted 18 June 2008 相似文献