共查询到20条相似文献,搜索用时 15 毫秒
1.
Smith NJ Chan HW Osborne JE Thomas WG Hannan RD 《Cellular and molecular life sciences : CMLS》2004,61(21):2695-2703
Activation of the type 1 angiotensin II receptor (AT(1)R) is associated with the aetiology of left ventricular hypertrophy, although the exact intracellular signalling mechanism(s) remain unclear. Transactivation of the epidermal growth factor receptor (EGFR) has emerged as a central mechanism by which the G protein-coupled AT(1)R, which lacks intrinsic tyrosine kinase activity, can stimulate the mitogen-activated protein kinase signalling pathways thought to mediate cardiac hypertrophy. Current studies support a model whereby AT(1)R-dependent transactivation of EGFRs on cardiomyocytes involves stimulation of membrane-bound metalloproteases, which in turn cleave EGFR ligands such as heparin-binding EGF from a plasma membrane-associated precursor. Numerous aspects of the 'triple membrane-passing signalling' paradigm of AT(1)R-induced EGFR transactivation remain to be characterised, including the identity of the specific metalloproteases involved, the intracellular mechanism for their activation and the exact EGFR subtypes required. Here we examine how 'hijacking' of the EGFR might explain the ability of the AT(1)R to elicit the temporally and qualitatively diverse responses characteristic of the hypertrophic phenotype, and discuss the ramifications of delineating these pathways for the development of new therapeutic strategies to combat cardiac hypertrophy. 相似文献
2.
Functions and malfunctions of the tau proteins 总被引:9,自引:1,他引:8
The tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they
play major regulatory roles in the organization and integrity of the cytoskeleton network. Neurofibrillary changes of abnormally
hyperphosphorylated tau are a key lesion in Alzheimer's disease and a number of other tauopathies. However, despite an ever-increasing
body of data on the changes which tau undergoes in disease, its role regarding the fundamental disease process is still unclear.
Moreover, conceptions of tau functions continue to evolve, which complicates an understanding of its role in the disease process.
This review attempts to summarize data on the role of tau proteins in the context of both normal cellular function and dysfunction.
Furthermore, we try to develop a mechanistic framework for the involvement of tau during the disease process. The review closes
with a look towards various approaches to elucidate the functions and malfunctions of tau.
Received 21 June 2002; received after revision 24 July 2002; accepted 29 July 2002
RID="*"
ID="*"Corresponding author. 相似文献
3.
N-acetylglucosaminyltransferase V modifies the signaling pathway of epidermal growth factor receptor 总被引:3,自引:0,他引:3
Guo P Wang QY Guo HB Shen ZH Chen HL 《Cellular and molecular life sciences : CMLS》2004,61(14):1795-1804
Transfection of sense cDNA of N-acetylglucosamyltransferase V (GnTV-S) into human H7721 hepatocarcinoma cells
resulted in an increase in the N-acetylglucosamine1,6mannose1,3- branch (GnT-V product) on the
N-glycans of epidermal growth factor (EGF) receptor (EGFR), and promotion of its EGF binding and tyrosine
autophosphorylation, but showed little effect on the expression of EGFR protein. The phosphorylation at T308,
S473 and tyrosine residue(s) and the activity of protein kinase B (Akt/PKB) as well as the phosphorylation of
p42/44 mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK) before and after EGF stimulation were
concomitantly increased. Conversely, in the antisense GnT-V (GnTV-AS)-transfected H7721 cells, all the results
were the reverse of those with GnTV-S-transfected cells. After the cells were treated with 1-deoxymannojirimycin,
an inhibitor of N-glycan processing at high mannose, or antibody against the extracellular glycan domain of EGFR,
the differences in PKB activity, p42/44 MAPK and MEK phosphorylation among GnTV-S-, GnTV-AS- and mock-transfected
cells were significantly attenuated. These findings indicate that the altered expression of GnT-V will change the
glycan structure and function of EGFR, which may modify downstream signal transduction.Received 24 March 2004; received after revision 1 May 2004; accepted 25 May 2004 相似文献
4.
Gabriele Eden Marco Archinti Ralitsa Arnaudova Giuseppina Andreotti Andrea Motta Federico Furlan Valentina Citro Maria Vittoria Cubellis Bernard Degryse 《Cellular and molecular life sciences : CMLS》2018,75(10):1889-1907
The urokinase receptor (uPAR) stimulates cell proliferation by forming a macromolecular complex with αvβ3 integrin and the epidermal growth factor receptor (EGFR, ErbB1 or HER1) that we name the uPAR proliferasome. uPAR transactivates EGFR, which in turn mediates uPAR-initiated mitogenic signal to the cell. EGFR activation and EGFR-dependent cell growth are blocked in the absence of uPAR expression or when uPAR activity is inhibited by antibodies against either uPAR or EGFR. The mitogenic sequence of uPAR corresponds to the D2A motif present in domain 2. NMR analysis revealed that D2A synthetic peptide has a particular three-dimensional structure, which is atypical for short peptides. D2A peptide is as effective as EGF in promoting EGFR phosphorylation and cell proliferation that were inhibited by AG1478, a specific inhibitor of the tyrosine kinase activity of EGFR. Both D2A and EGF failed to induce proliferation of NR6-EGFR-K721A cells expressing a kinase-defective mutant of EGFR. Moreover, D2A peptide and EGF phosphorylate ERK demonstrating the involvement of the MAP kinase signalling pathway. Altogether, this study reveals the importance of sequence D2A of uPAR, and the interdependence of uPAR and EGFR. 相似文献
5.
MDA-MB-468 is a human mammary adenocarcinoma cell line that overexpresses the epidermal growth factor (EGF) receptor and
undergoes programmed cell death (apoptosis) in response to EGF treatment. Programmed cell death was shown to be greatly enhanced
when cells were growth-arrested prior to EGF treatment. Apoptosis was characterized by an initial rounding up and detachment
of the cells from their substrate starting about 12 h after EGF treatment, followed by chromatin condensation, nuclear fragmentation
and oligonucleosomal fragmentation of the DNA at about 24 to 48 h. Cell death was dependent on de novo protein synthesis.
We found a rapid induction of c-fos, c-jun and junB at the mRNA level after about 30 min of EGF treatment and a more delayed upregulation of fosB and fra-1. The junD gene was expressed in the absence of EGF, and it was moderately induced within 30 min of growth factor addition. The increase
of the different fos and jun mRNAs were paralleled by an increase of activator protein-1 (AP-1) DNA binding activity. A characterization of the AP-1 complex
revealed similar levels of several Fos and Jun proteins. Based on the kinetics of AP-1 accumulation and cell death, it seems
likely that AP-1 contributes to the apoptotic cell death of EGF receptor-overexpressing MDA-MB-468 cells.
Received 21 July 1997; received after revision 6 November 1997; accepted 6 November 1997 相似文献
6.
Karen Forbes Laura Skinner John D. Aplin Melissa Westwood 《Cellular and molecular life sciences : CMLS》2012,69(23):4029-4040
Insulin-like growth factors (IGFs) influence placental cell (cytotrophoblast) kinetics. We recently reported that the protein tyrosine phosphatase (PTP) SHP-2 positively regulates IGF actions in the placenta. In other systems, the closely related PTP, SHP-1, functions as a negative regulator of signaling events but its role in the placenta is still unknown. We examined the hypothesis that SHP-1 negatively regulates IGF actions in the human placenta. Immunohistochemical (IHC) analysis demonstrated that SHP-1 is abundant in cytotrophoblast. SHP-1 expression was decreased in first-trimester placental explants using siRNA; knockdown did not alter IGF-induced proliferation but it significantly enhanced proliferation in serum-free conditions, revealing that placental growth is endogenously regulated. Candidate regulators were determined by using antibody arrays, Western blotting, and IHC to examine the activation status of multiple receptor tyrosine kinases (RTKs) in SHP-1-depleted explants; amongst the alterations observed was enhanced activation of EGFR, suggesting that SHP-1 may interact with EGFR to inhibit proliferation. The EGFR tyrosine kinase inhibitor PD153035 reversed the elevated proliferation seen in the absence of SHP-1. This study demonstrates a role for SHP-1 in human trophoblast turnover and establishes SHP-1 as a negative regulator of EGFR activation. Targeting placental SHP-1 expression may provide therapeutic benefits in common pregnancy conditions with abnormal trophoblast proliferation. 相似文献
7.
Bennasroune A Gardin A Auzan C Clauser E Dirrig-Grosch S Meira M Appert-Collin A Aunis D Crémel G Hubert P 《Cellular and molecular life sciences : CMLS》2005,62(18):2124-2131
Receptor tyrosine kinases play essential roles in cell proliferation and differentiation. We have recently shown that peptides corresponding to the transmembrane domains of the epidermal growth factor (EGF) and ErbB2 receptors inhibit their corresponding receptor activation in cancer cell lines. We extend this observation to cells transfected with chimeric insulin receptors where the transmembrane domain has been replaced by that of the EGF receptor or a mutated Erb2 domain. Peptides corresponding to the transmembrane domains of the EGF receptor and ErbB2 are able to inhibit specifically the autophosphorylation of insulin receptors with the corresponding domain. This inhibitory effect is correlated with the propensity of the different transmembrane domains to self-associate in a genetic reporter assay. Thus, our data strengthen the notion that transmembrane domains are involved in erbB receptor activation, and that these receptors can be modulated by inhibiting proteinprotein interactions within the membrane.Received 25 May 2005; received after revision 13 July 2005; accepted 22 July 2005 相似文献
8.
Amelogenin gene splice products: potential signaling molecules 总被引:3,自引:0,他引:3
Veis A 《Cellular and molecular life sciences : CMLS》2003,60(1):38-55
The amelogenins, the major proteins of the developing tooth enamel matrix, are highly conserved throughout most species studied.
The gene structure is similar, with a set of seven exons and intervening introns, and remarkable conservation of particular
exon sizes over divergent species. Studies of exon skipping and consequent alternative gene splicing suggest that, in vertebrates,
exon definition is crucial. In this mechanism, exon size is important. If too small, an exon can be readily skipped, if too
large, internal cryptic splice sites may be utilized. Other factors, such as intron length and specific nucleotide sequences
at the splice boundaries also modulate splicing efficiency, but amelogenin gene splicing conforms well to the generalized
exon length model. Exons 1, 2 and 7 are not subject to splicing that affects the secreted protein product, but exons 3, 4
and 5 are at the lower boundary of exon size, rendering them, 4 and 5 especially, subject to skipping. On the other hand,
exon 6 is very long and has cryptic splicing sites that can be used. In the mouse, nine distinct splice product proteins have
been detected. The question now is the functions of these products. The larger forms, those that contain the intact proline-rich,
hydrophobic exon 6 domains, are important for enamel mineralization. Recent work suggests that the small proteins resulting
from deletion of a major part of amelogenin gene exon 6 via utilization of a cryptic site may have signal transduction
functions during tooth development. Furthermore, new work also suggests that odontoblasts transiently express the small amelogenins
during the period that epithelial-mesenchymal signaling between preodontoblasts and preameloblasts determines the course of
tooth development. The same peptides have been demonstrated to act on non-odontogenic cells and effect their phenotypic expression
patterns in vitro, and to induce bone formation in implants in vivo.
Received 20 March 2002; received after revision 2 July 2002; accepted 3 July 2002 相似文献
9.
Species-specific cell adhesion in marine sponges is mediated by a new family of modular proteoglycans whose general supramolecular
structure resembles that of hyalectans. However, neither their protein nor their glycan moieties have significant sequence
homology to other proteoglycans, despite having protein subunits equivalent to link proteins and to proteoglycan monomer core
proteins, and glycan subunits equivalent to hyaluronan and to the glycosaminoglycans of hyalectans. In some species, these
molecular components are assembled into a structure with a circular core formed by the link protein- and hyaluronan-like subunits.
Besides their involvement in cell adhesion, these sponge proteoglycans, for which we propose the term spongicans, participate
in signal transduction processes and are suspected to play a role in sponge self-nonself recognition. Their in vivo roles
and the mild methods used to purify large amounts of functionally active spongicans make them ideal models to study the functions
and possible new applications of proteoglycans in biomedical research.
Received 21 May 2002; received after revision 5 July 2002; accepted 10 July 2002
RID="*"
ID="*"Corresponding author. 相似文献
10.
Anti-DNA antibodies: aspects of structure and pathogenicity 总被引:4,自引:0,他引:4
Anti-DNA antibodies contribute to the pathology of systemic lupus erythematosus. Their depositon in tissue lesions could
result from localization of preformed immune complexes of antibodies with DNA or nucleosomes, or from cross-reaction of anti-DNA
antibodies directly with tissue proteins. Structural analyses contribute to understanding their pathogenic potential. Primary
structures of lupus immunoglobulin G double-stranded DNA-binding autoantibodies are determined by immunoglobulin genes with
mutated variable region segments, indicative of selection by immunizing antigen. Arginine, lysine and asparagine residues
in complementarity-determining region favor DNA binding. Heavy-chain variable regions make major contributions to DNA binding;
affinity and specificity of binding are modulated or can be abrogated by the light-chain variable domain. Crytallographic
structure is known for a few antibody-DNA complexes and several ligand-free Fab fragments. Computer modeling supplements this
limited information. Structural information of lupus antibody interactions with both DNA and cross-reacting molecules will
support use of ligands to inhibit tissue deposition of the antibodies and prevent lesion formation in lupus.
Received 4 July 2002; accepted 23 July 2002
RID="*"
ID="*"Corresponding author. 相似文献
11.
The processing and presentation of endogenous and exogenous antigen by Schwann cells in vitro 总被引:1,自引:0,他引:1
Lilje O 《Cellular and molecular life sciences : CMLS》2002,59(12):2191-2198
The expression of major histocomatibility complex class II in vitro and in vivo by Schwann cells indicates a potential facultative
role of Schwann cells in the presentation of antigen to neuritogenic T cells during inflammatory demyelinating neuropathies.
Using a T cell proliferation assay, this study demonstrated that processing and presentation of endogenous and exogenous antigen
by Schwann cells influences T cell proliferation. Statistical analysis of proliferation and its relation to processing and
presentation of antigen by Schwann cells had not been previously addressed. Different combinations of factors including treatment
of cultures (untreated, irradiated or fixed), concentration of exogenous antigen (0 or 40 μmg/ml), the presence of interferon-γ
and the timing of exogenous antigen addition influence the proliferation P2-specific, non-mammalian protein ovalbumin-specific T cell lines and naive T cells.
Received 25 July 2002; received after revision 9 September 2002; accepted 7 October 2002 相似文献
12.
Low molecular weight protein tyrosine phosphatases (LMW-PTPs) are a family of 18-kDa enzymes involved in cell growth regulation.
Despite very limited sequence similarity to the PTP superfamily, they display a conserved signature motif in the catalytic
site. LMW-PTP associates and dephosphorylate many growth factor receptors, such as platelet-derived growth factor receptor
(PDGF-r), insulin receptor and ephrin receptor, thus downregulating many of the tyrosine kinase receptor functions that lead
to cell division. In particular, LMW-PTP acts on both growth-factor-induced mitosis, through dephosphorylation of activated
PDGF-r, and on cytoskeleton rearrangement, through dephosphorylation of p190RhoGAP and the consequent regulation of the small
GTPase Rho. LMW-PTP activity is modulated by tyrosine phosphorylation on two specific residues, each of them with specific
characteristics. LMW-PTP activity on specific substrates depends also on its localization. Moreover, LMW-PTP is reversibly
oxidized during growth factor signaling, leading to inhibition of its enzymatic activity. Recovery of phosphatase activity
depends on the availability of reduced glutathione and involves the formation of an S–S bridge between the two catalytic site
cysteines. Furthermore, studies on the redox state of LMW-PTP in contact-inhibited cells and in mature myoblasts suggest that
LMW-PTP is a general and versatile modulator of growth inhibition.
Received 17 January 2002; received after revision 22 March 2002; accepted 26 March 2002 相似文献
13.
Penkowa M Espejo C Martínez-Cáceres EM Montalban X Hidalgo J 《Cellular and molecular life sciences : CMLS》2003,60(1):185-197
Metallothioneins I+II (MT-I+II) are antioxidant, neuroprotective factors. We previously showed that MT-I+II deficiency during
experimental autoimmune encephalomyelitis (EAE) leads to increased disease incidence and clinical symptoms. Moreover, the
inflammatory response of macrophages and T cells, oxidative stress, and apoptotic cell death during EAE were increased by
MT-I+II deficiency. We now show for the first time that demyelination and axonal damage are significantly increased in MT-I+II
deficient mice during EAE. Furthermore, oligodendroglial regeneration, growth cone formation, and tissue repair including
expression of trophic factors were significantly reduced in MT-I+II-deficient mice during EAE. Accordingly, MT-I+II have protective
and regenerative roles in the brain.
Received 31 October 2002; received after revision 23 November 2002; accepted 26 November 2002
RID="*"
ID="*"Corresponding author. M. Penkowa and C. Espejo contributed equally to this paper. 相似文献
14.
Cellulase genes of Pseudotrichonympha grassii (Hypermastigida: Eucomonymphidae), the symbiotic flagellate in the hindgut of the wood-feeding termite Coptotermes formosanus, were isolated and characterized. The nucleotide sequences of the major cellulase component in the hindgut of C. formosanus were determined based on its N-terminal amino acid sequence. The five isolated nucleotide sequences (PgCBH-homos) had an open reading frame of 1350 bp showing similarity to catalytic domains of glycoside hydrolase family (GHF) 7 members,
and primary structure comparison with GHF7 members whose tertiary structures are well-characterized revealed the overall similarity
between PgCBH-homo and the catalytic domain of a processive cellulase Cel7A (formerly CBHI) from the aerobic fungus Trichoderma reesei. Functional expression of PgCBH-homos in Escherichia coli, using the carboxymethylcellulose-Congo red assay, demonstrated the actual cellulolytic activity of PgCBH-homo. RT-PCR showed
that PgCBH-homos were expressed, from the three flagellates in the hindgut, specifically in P. grassii.
Received 10 July 2002; accepted 26 July 2002
RID="*"
ID="*"Corresponding author. 相似文献
15.
This review begins with a general presentation of the new paradigm of drug discovery, with its emphasis on the rapid identification
and elimination of compounds with unsuitable physicochemical and pharmacokinetic properties. The focus of the paper is on
the various experimental methods used to determine such key physicochemical properties as ionization, lipophilicity and distribution
in isotropic and anisotropic systems, solubility, and permeability across artificial membranes. Both traditional and high-throughput
methods are presented and their limits highlighted. The text concludes with the trade-off between quantity/speed in high-throughput
screening techniques versus greater data quality in the more labor-intensive methods.
Received 23 April 2002; received after revision 25 June 2002; accepted 11 July 2002
RID="*"
ID="*"Corresponding author. 相似文献
16.
Neuropeptide Y: the universal soldier 总被引:13,自引:0,他引:13
The peptidic neurotransmitter neuropeptide Y (NPY) has received great attention because it has been implicated in the regulation
of several organ systems. In particular, NPY is involved in the regulatory loops that control food intake in the hypothalamus
and appears also to be important for regulating the activity of neuroendocrine axes under poor metabolic conditions. Furthermore,
NPY exerts vasoconstrictive action on the vasculature and potentiates the actions of many other vasoconstrictors. In addition,
it was demonstrated to have trophic properties and could therefore contribute to cardiovascular remodeling. These various
effects plus a number of others make NPY an attractive target for the potential treatment of human diseases, such as obesity,
metabolic disorders, hypertension and heart failure.
Received 17 July 2002; received after revision 7 November 2002; accepted 29 November 2002
RID="*"
ID="*"Corresponding author. 相似文献
17.
Faust M Günther J Morgenstern E Montenarh M Götz C 《Cellular and molecular life sciences : CMLS》2002,59(12):2155-2164
The protein kinase CK2 holoenzyme is composed of two regulatory β subunits and two catalytic α or α' subunits. Although experimental
evidence for involvement of the enzyme in the regulation of cell proliferation is accumulating, the exact mechanism of its
action is still unclear. The subcellular localization of the enzyme may be a key to its function. We have recently shown that
the CK2 holoenzyme is tightly associated with the Golgi complex and the endoplasmic reticulum. Centrosomes, which organize
spindle formation during the cell cycle and microtubule cytoskeleton formation and, thereby, the location and orientation
of different organelles in the cell, are in close vicinity to the Golgi complex. Because several kinases and phosphatases
have been described to regulate the functions of the centrosome, we analysed the association of CK2 with these organelles.
Using biochemical cell fractionation and coimmunoprecipitation, we never found the holoenzyme but only the catalytic asubunits
associated with the centrosome. These data were confirmed by immunoelectron microscopy. Thus, the present data point to a
particular role of the catalytic α and α' subunit of protein kinase CK2, which may be different from their roles in the holoenzyme.
Received 2 August 2002; received after revision 2 October 2002; accepted 22 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
18.
Prosperi-Meys C de Seny D Llabres G Galleni M Lamotte-Brasseur J 《Cellular and molecular life sciences : CMLS》2002,59(12):2136-2143
Increased resistance to β-lactam antibiotics is mainly due to β-lactamases. X-ray structures of zinc β-lactamases unraveled
the coordination of the metal ions, but their mode of action remains unclear. Recently, enzymes in which one of the zinc ligands
was mutated have been characterized and their catalytic activity against several β-lactam antibiotics measured. A molecular
modeling study of these enzymes was performed here to explain the catalytic activity of the mutants. Coordination around the
zinc ions influences the way the tetrahedral intermediate is bound; any modification influences the first recognition of the
substrate by the enzyme. For all the studied mutants, at least one of the interactions fails, inducing a loss of catalytic
efficiency compared to the wild type. The present studies show that the enzyme cavity is a structure of high plasticity both
structurally and mechanistically and that local modifications may propagate its effects far from the mutated amino
acid.
Received 28 August 2002; received after revision 22 October 2002; accepted 24 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
19.
Statins: the new aspirin? 总被引:10,自引:0,他引:10
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been described as the principal and
the most effective class of drug to reduce serum cholesterol levels. Statin therapies have been shown to reduce cardiovascular
events, including myocardial infarction, stroke, and death, significantly, by altering vascular atherosclerosis development
in patients with or without coronary artery disease symptoms. Extensive use of statins has led to the increase of some undesirable
effects that are heavily counterbalanced by the benefits. Indeed, pleiotropic effects extend far beyond cholesterol reduction
and involve non-lipid-related mechanisms that modify endothelial functions, immunoinflammatory responses, smooth muscle cell
activation, proliferation and migration, atherosclerotic plaque stability, and thrombus formation. In this review, we describe
in detail the targets and mechanisms of action of statins.
Received 6 June 2002; received after revision 6 September 2002; accepted 6 September 2002
RID="*"
ID="*"Corresponding author. 相似文献
20.
Retinoic acid modulates gap junctional intercellular communication in hepatocytes and hepatoma cells 总被引:3,自引:0,他引:3
Ara C Massimi M Devirgiliis Conti L 《Cellular and molecular life sciences : CMLS》2002,59(10):1758-1765
Gap junctional communication permits the direct exchange of small molecules and ions and has been implicated in tissue homeostasis/metabolite
exchange. The lack of gap junctional intercellular communication (GJIC) plays important roles in the promotion and progression
of carcinogenesis. In the present study, we demonstrate that treatment of human hepatoma Hep G2 cells with retinoic acid (RA)
results in increased amounts and phosphorylation of connexins, their stabilisation in plasma membrane plaques and enhanced
GJIC. In cultured fetal hepatocytes, which represent a non-transformed, proliferating and incompletely differentiated liver
system, the effects of RA are limited to the establishment of connexin in areas of cell-cell contact and the improvement of
GJIC. This suggests that modulation of cell-cell channel communication by RA occurs differently in these two experimental
models: while RA is able to revert cell transformation in Hep G2 cells, in fetal hepatocytes it may induce the expression
of a more differentiated phenotype.
Received 19 June 2002; received after revision 29 July 2002; accepted 8 August 2002
RID="*"
ID="*"Corresponding author. 相似文献