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1.
Telomeres and telomerase as targets for cancer therapy 总被引:3,自引:0,他引:3
Telomeres are protective structures located at the ends of all eukaryotic chromosomes. Telomere shortening upon cell division
restricts the proliferative capacity of most normal human cells due to the lack of telomerase, an enzyme synthesizing telomeric
DNA de novo. Since most tumor cells are reliant on the activity of telomerase to maintain the stability of predominantly short individual
telomeres, inhibition of this enzyme presents an attractive approach for a mechanism-based anticancer therapy. Here, we review
advances and obstacles in targeting telomerase and telomeres and discuss potential applications of such approaches for the
clinic.
Received 9 November 2006; received after revision 8 December 2006; accepted 17 January 2007 相似文献
2.
Uhland K 《Cellular and molecular life sciences : CMLS》2006,63(24):2968-2978
Tumor progression and metastasis are the pathologic effects of uncontrolled or deregulated invasive growth, a process in which
proteases play a fundamental role. They mediate the degradation of extracellular matrix components and intercellular cohesive
structures to allow migration of the cells into the extracellular environment and activate growth and angiogenic factors.
In addition to metalloproteases and the plasminogen activation system, another protease, matriptase, contributes substantially
to these processes. Matriptase is a type II transmembrane trypsin-like serine protease that is expressed by cells of epithelial
origin and is overexpressed in a variety of human cancers. It has been suggested that this protease not only facilitates cellular
invasiveness but may also activate oncogenic pathways. This review summarizes current knowledge about matriptase, its putative
role in tumor initiation and progression, and its potential as a novel target in anti-cancer therapy.
Received 29 June 2006; received after revision 1 August 2006; accepted 19 September 2006 相似文献
3.
Annexin V was originally identified as a collagen-binding protein called anchorin CII and was isolated from chondrocyte membranes
by affinity chromatography on native type II collagen. The binding of annexin V to native collagen type II is stable at physiological
ionic strength when annexin V is reconstituted in liposomes. The binding to native collagen types II and X, and to some extent
to type I as well, was confirmed using recombinant annexin V. A physiological role for annexin V interactions with extracellular
collagen is consistent with the localization of annexin V on the outer cell surface of chondrocytes, microvilli of hypertrophic
chondrocytes, fibroblasts and osteoblasts. A breakthrough in our understanding of the function of annexin V was made with
the discovery of its calcium channel activity. At least one of several putative functions of annexin V became obvious from
studies on matrix vesicles derived from calcifying cartilage. It was found that calcium uptake by matrix vesicles depend on
collagen type II and type X binding to annexin V in the vesicles and was lost when collagens were digested with collagenase;
calcium influx was reconstituted after adding back native collagen II or V. These findings indicate that annexin V plays a
major role in matrix vesicle-initiated cartilage calcification as a collagen-regulated calcium channel. 相似文献
4.
Barratt G 《Cellular and molecular life sciences : CMLS》2003,60(1):21-37
Colloidal drug carriers such as liposomes and nanoparticles are able to modify the distribution of an associated substance.
They can therefore be used to improve the therapeutic index of drugs by increasing their efficacy and/or reducing their toxicity.
If these delivery systems are carefully designed with respect to the target and route of administration, they may provide
one solution to some of the delivery problems posed by new classes of active molecules such as peptides, proteins, genes,
and oligonucleotides. They may also extend the therapeutic potential of established drugs such as doxorubicin and amphotericin
B. This article discusses the use of colloidal, particulate carrier systems (25 nm to 1 μm in diameter) in such applications.
In particular, systems which show diminished uptake by mononuclear phagocytes are described. Specific targeting of carriers
to particular tissues or cells is also considered.
Received 8 April 2002; received after revision 25 June 2002; accepted 26 June 2002 相似文献
5.
Receptor communication within the lymphocyte plasma membrane: a role for the thrombospondin family of matricellular proteins 总被引:1,自引:0,他引:1
Lymphocytes, the principal cells of the immune system, carry out immune surveillance throughout the body by their unique capacity
to constantly reposition themselves between a free-floating vascular state and a tissue state characterized by migration and
frequent adhesive interactions with endothelial cells and components of the extracellular matrix. Therefore, mechanisms co-ordinating
adhesion and migration with signals delivered through antigen recognition probably play a pivotal role for the regulation
of lymphocyte behaviour and function. Endogenous thrombospondin-1 (TSP-1) seems to be the hub in such a mechanism for autocrine
regulation of T cell adhesion and migration. TSP-1 functions as a mediator of cis interaction of vital receptors within the T lymphocyte plasma membrane, including integrins, low density lipoprotein receptor-related
protein, calreticulin and integrin-associated protein.
Received 1 June 2006; received after revision 28 June 2006; accepted 11 October 2006 相似文献
6.
Chiara Riganti Iris C. Salaroglio Martha L. Pinzòn-Daza Valentina Caldera Ivana Campia Joanna Kopecka Marta Mellai Laura Annovazzi Pierre-Olivier Couraud Amalia Bosia Dario Ghigo Davide Schiffer 《Cellular and molecular life sciences : CMLS》2014,71(3):499-516
Low delivery of many anticancer drugs across the blood–brain barrier (BBB) is a limitation to the success of chemotherapy in glioblastoma. This is because of the high levels of ATP-binding cassette transporters like P-glycoprotein (Pgp/ABCB1), which effluxes drugs back to the bloodstream. Temozolomide is one of the few agents able to cross the BBB; its effects on BBB cells permeability and Pgp activity are not known. We found that temozolomide, at therapeutic concentration, increased the transport of Pgp substrates across human brain microvascular endothelial cells and decreased the expression of Pgp. By methylating the promoter of Wnt3 gene, temozolomide lowers the endogenous synthesis of Wnt3 in BBB cells, disrupts the Wnt3/glycogen synthase kinase 3/β-catenin signaling, and reduces the binding of β-catenin on the promoter of mdr1 gene, which encodes for Pgp. In co-culture models of BBB cells and human glioblastoma cells, pre-treatment with temozolomide increases the delivery, cytotoxicity, and antiproliferative effects of doxorubicin, vinblastine, and topotecan, three substrates of Pgp that are usually poorly delivered across BBB. Our work suggests that temozolomide increases the BBB permeability of drugs that are normally effluxed by Pgp back to the bloodstream. These findings may pave the way to new combinatorial chemotherapy schemes in glioblastoma. 相似文献
7.
S. P. Dufrane A. Poss E. Goormaghtigh J. M. Ruysschaert 《Cellular and molecular life sciences : CMLS》1981,37(5):524-525
Summary We present evidence that cholesterol mediates thyrotropin binding to liposomes containing GT1 ganglioside. Thyrotropin fixation is maximal at 22% of cholesterol. This result suggests that the gangliosides' organization in the lipid matrix modulates their interaction with the glycoprotein hormone. 相似文献
8.
Kertész A Váradi G Tóth GK Fajka-Boja R Monostori E Sármay G 《Cellular and molecular life sciences : CMLS》2006,63(22):2682-2693
Phosphopeptides interacting with src homology 2 (SH2) domains can activate essential signaling enzymes in vitro. When delivered to cells, they may disrupt protein-protein interactions, thereby influencing intracellular signaling. We
showed earlier that phosphopeptides corresponding to the inhibitory motif of Fcγ receptor IIb and a motif of the Grb2-associated
binder 1 adaptor protein activate SH2-containing tyrosine phosphatase 2 in vitro. To study the ex vivo effects of these peptides, we have now compared different methods for peptide delivery: (i) permeabilization of the target
cells and (ii) the use of cell-permeable vectors, which are potentially able to transport biologically active compounds into
B cells. We found octanoyl-Arg8 to be an optimal carrier for the delivery of phosphopeptides to the cells. With this strategy, the function of cell-permeable
SHP-2-binding phosphopeptides was analyzed. These peptides modulated the protein phosphorylation in B cells in a dose- and
time-dependent manner.
Received 27 July 2006; received after revision 4 September 2006; accepted 18 September 2006 相似文献
9.
Enhanced heparan sulfate proteoglycan-mediated uptake of cell-penetrating peptide-modified liposomes
Marty C Meylan C Schott H Ballmer-Hofer K Schwendener RA 《Cellular and molecular life sciences : CMLS》2004,61(14):1785-1794
Protein transduction domains (PTDs) are used to enhance cellular uptake of drugs, proteins, polynucleotides
or liposomes. In this study, functionalized Antennapedia (Antp, aa 43–-58) and HIV Tat (aa 47–57)
peptides were coupled to small unilamellar liposomes via thiol-maleimide linkage. Modified liposomes showed higher
uptake into a panel of cell lines including tumor and dendritic cells than unmodified control liposomes. Liposome
uptake was time and concentration dependent as analyzed by flow cytometry and live-cell microscopy. At least 100
PTD molecules per small unilamellar liposome (100 ± 30 nm) were necessary for efficient translocation into
cells. Cellular uptake of PTD-modified liposomes was 15- to 25-fold increased compared to unmodified liposomes and
was inhibited by preincubation of liposomes with heparin. Glycosaminoglycan-deficient CHO cells showed dramatically
reduced cell association of PTD-modified liposomes, confirming the important role of heparan sulfate proteoglycans
in PTD-mediated uptake. Antp-liposomes used as carriers of the cytotoxic drug
N4-octadecyl-1--D-arabinofuranosylcytosine-(5- 5)-3-C-ethinylcytidine
showed a reduction of the IC50 by 70% on B16F1 melanoma cells compared with unmodified
liposomes. PTD-functionalized liposomes, particularly Antp-liposomes, represent an interesting novel carrier
system for enhanced cell-specific delivery of a large variety of liposome-entrapped molecules.Received 16 April 2004; received after revision 13 May 2004; accepted 25 May 2004 相似文献
10.
Targeted polymeric micelles for delivery of poorly soluble drugs 总被引:17,自引:0,他引:17
Torchilin VP 《Cellular and molecular life sciences : CMLS》2004,61(19-20):2549-2559
Polymeric micelles (micelles formed by amphiphilic block copolymers) demonstrate a series of attractive properties as drug carriers, such as high stability both in vitro and in vivo and good biocompatibility, and can be successfully used for the solubilization of various poorly soluble pharmaceuticals. These micelles can also be used as targeted drug delivery systems. The targeting can be achieved via the enhanced permeability and retention effect (into the areas with the compromised vasculature), by making micelles of stimuli-responsive amphiphilic block copolymers, or by attaching specific targeting ligand molecules to the micelle surface. Immunomicelles prepared by coupling monoclonal antibody molecules to p-nitrophenylcarbonyl groups on the water-exposed termini of the micelle corona-forming blocks demonstrate high binding specificity and targetability. Immunomicelles prepared with cancer-specific monoclonal antibody 2C5 specifically bind to different cancer cells in vitro and demonstrate increased therapeutic activity in vivo. This new family of pharmaceutical carriers can be used for the solubilization and targeted delivery of poorly soluble drugs to various pathological sites in the body. 相似文献
11.
Shapiro JL Wen X Okamoto CT Wang HJ Lyngstadaas SP Goldberg M Snead ML Paine ML 《Cellular and molecular life sciences : CMLS》2007,64(2):244-256
Proteins of the developing enamel matrix include amelogenin, ameloblastin and enamelin. Of these three proteins amelogenin
predominates. Protein-protein interactions are likely to occur at the ameloblast Tomes’ processes between membrane-bound proteins
and secreted enamel matrix proteins. Such protein-protein interactions could be associated with cell signaling or endocytosis.
CD63 and Lamp1 are ubiquitously expressed, are lysosomal integral membrane proteins, and localize to the plasma membrane.
CD63 and Lamp1 interact with amelogenin in vitro. In this study our objective was to study the molecular events of intercellular trafficking of an exogenous source of amelogenin,
and related this movement to the spatiotemporal expression of CD63 and Lamp1 using various cell lineages. Exogenously added
amelogenin moves rapidly into the cell into established Lamp1-positive vesicles that subsequently localize to the perinuclear
region. These data indicate a possible mechanism by which amelogenin, or degraded amelogenin peptides, are removed from the
extracellular matrix during enamel formation and maturation.
Received 27 September 2006; received after revision 24 November 2006; accepted 5 December 2006 相似文献
12.
Fabre AC Vantourout P Champagne E Tercé F Rolland C Perret B Collet X Barbaras R Martinez LO 《Cellular and molecular life sciences : CMLS》2006,63(23):2829-2837
We have previously demonstrated on human hepatocytes that apolipoprotein A-I binding to an ecto-F1-ATPase stimulates the production of extracellular ADP that activates a P2Y13-mediated high-density lipoprotein (HDL) endocytosis pathway. Therefore, we investigated the mechanisms controlling the extracellular
ATP/ADP level in hepatic cell lines and primary cultures to determine their impact on HDL endocytosis. Here we show that addition
of ADP to the cell culture medium induced extracellular ATP production that was due to adenylate kinase
and nucleoside diphosphokinase
activities, but not to ATP synthase activity. We further observed that in vitro modulation of both ecto-NDPK and AK activities could regulate the ADP-dependent HDL endocytosis. But interestingly, only
AK appeared to naturally participate in the pathway by consuming the ADP generated by the ecto-F1-ATPase. Thus controlling the extracellular ADP level is a potential target for reverse cholesterol transport regulation.
Received 13 July 2006; received after revision 29 August 2006; accepted 19 September 2006 相似文献
13.
Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue 总被引:5,自引:0,他引:5
The dystrophin glycoprotein complex (DGC) is a multimeric protein assembly associated with either the X-linked cytoskeletal
protein dystrophin or its autosomal homologue utrophin. In striated muscle cells, the DGC links the extracellular matrix to
the actin cytoskeleton and mediates three major functions: structural stability of the plasma membrane, ion homeostasis, and
transmembrane signaling. Mutations affecting the DGC underlie major forms of congenital muscle dystrophies. The DGC is prominent
also in the central and peripheral nervous system and in tissues with a secretory function or which form barriers between
functional compartments, such as the blood-brain barrier, choroid plexus, or kidney. A considerable molecular heterogeneity
arises from cell-specific expression of its constituent proteins, notably short C-terminal isoforms of dystrophin. Experimentally,
the generation of mice carrying targeted gene deletions affecting the DGC has clarified the interdependence of DGC proteins
for assembly of the complex and revealed its importance for brain development and regulation of the ’milieu intérieur. Here,
we focus on recent studies of the DGC in brain, blood-brain barrier and choroid plexus, retina, and kidney and discuss the
role of dystrophin isoforms and utrophin for assembly of the complex in these tissues.
Received 4 October 2005; received after revision 14 March 2006; accepted 5 April 2006 相似文献
14.
Delivery of macromolecules into living cells by arginine-rich cell penetrating peptides (AR-CPPs) is an important new avenue
for the development of novel therapeutic strategies. However, to date the mechanism of this delivery remains elusive. Recent
data implicate endocytosis in the internalization of AR-CPPs and their macromolecular cargo and also indicate limited delivery
of macromolecules into the cell cytoplasm and nucleus. Different types of endocytosis – clathrin-dependent endocytosis, raft/caveolin-dependent
endocytosis and macropinocytosis – are all implicated in the uptake of AR-CPPs and their cargo into different cells. Cationic
AR-CPPs dramatically increase uptake of conjugated molecules through efficient binding to surface proteoglycans. Whether this
increase in binding can assure delivery of a sufficient amount of functionally active macromolecules into the cytoplasm and
nucleus or whether there is a specific mechanism by which AR-CPPs facilitate the escape of conjugated cargo from endosomes
remains to be understood.
Received 30 June 2005; received after revision 9 August 2005; accepted 30 August 2005 相似文献
15.
Myelin basic protein: a multifunctional protein 总被引:1,自引:1,他引:0
Boggs JM 《Cellular and molecular life sciences : CMLS》2006,63(17):1945-1961
Myelin basic protein (MBP), the second most abundant protein in central nervous system myelin, is responsible for adhesion
of the cytosolic surfaces of multilayered compact myelin. A member of the ‘intrinsically disordered’ or conformationally adaptable
protein family, it also appears to have several other functions. It can interact with a number of polyanionic proteins including
actin, tubulin, Ca2+-calmodulin, and clathrin, and negatively charged lipids, and acquires structure on binding to them. It may act as a membrane
actin-binding protein, which might allow it to participate in transmission of extracellular signals to the cytoskeleton in
oligodendrocytes and tight junctions in myelin. Some size isoforms of MBP are transported into the nucleus and thus they may
also bind polynucleotides. Extracellular signals received by myelin or cultured oligodendrocytes cause changes in phosphorylation
of MBP, suggesting that MBP is also involved in signaling. Further study of this very abundant protein will reveal how it
is utilized by the oligodendrocyte and myelin for different purposes.
Received 2 March 2006; received after revision 12 April 2006; accepted 16 May 2006 相似文献
16.
Periostin is a matricellular protein that is composed of a multi-domain structure with an amino-terminal EMI domain, a tandem repeat of four FAS 1 domains, and a carboxyl-terminal domain. These distinct domains have been demonstrated to bind to many proteins including extracellular matrix proteins (Collagen type I and V, fibronectin, tenascin, and laminin), matricellular proteins (CCN3 and βig-h3), and enzymes that catalyze covalent crosslinking between extracellular matrix proteins (lysyl oxidase and BMP-1). Adjacent binding sites on periostin have been suggested to put the interacting proteins in close proximity, promoting intermolecular interactions between each protein, and leading to their assembly into extracellular architectures. These extracellular architectures determine the mechanochemical properties of connective tissues, in which periostin plays an important role in physiological homeostasis and disease progression. In this review, we introduce the proteins that interact with periostin, and discuss how the multi-domain structure of periostin functions as a scaffold for the assembly of interacting proteins, and how it underlies construction of highly sophisticated extracellular architectures. 相似文献
17.
K. J. Clemetson 《Cellular and molecular life sciences : CMLS》1998,54(6):499-501
Integrins are a family of adhesive receptors consisting of α- and β-subunits which attach cells together via adhesive protein ligands or bind cells to extracellular matrix. They are found on
virtually all cell types and link the external ligand to the cytoskeleton of the cell. Integrins also act as signal transducers
both from the outside of the cell to the interior and also inside-out. Their main functions are in recognition and in tight
but regulated binding. The series of reviews presented here cover both basic aspects of integrin function, including signal
transduction, snake disintegrins and structure and function of I-domains in some integrin α-subunits, as well as the role of integrins in diseases, cancer, inflammation and cardiovascular diseases. The search for suitable
inhibitors of integrins for treatment of these diseases and future prospects for their use are also discussed. 相似文献
18.
Hydroxyproline-rich glycoproteins in plant reproductive tissues: structure, functions and regulation 总被引:10,自引:0,他引:10
H. Wu B. de Graaf C. Mariani A.Y. Cheung 《Cellular and molecular life sciences : CMLS》2001,58(10):1418-1429
The plant reproductive process of pollination involves a series of interactions between the male gametophyte (the pollen
grain or pollen tube) and extracellular matrix (ECM) molecules secreted by different cell types along the pollen tube growth
pathway in the female organ, the pistil. These interactions are believed to signal and regulate the pollen tube growth process
to effect successful delivery of the sperm cells to the ovules where fertilization takes place. Hydroxyproline-rich glycoproteins
secreted by plant cells are believed to play a broad range of functions, ranging from providing structural integrity to mediating
cell-cell interactions and communication. The pistil and pollen tube ECM is enriched in these highly glycosylated proteins.
Our discussions here will focus on a number of these proteins for which most information has been available, from Nicotiana tabacum, its self-incompatible relative N. alata, and Zea mays. In addition, the regulation of the synthesis and glyco-modification of one of these proteins, TTS (transmitting tissue-specific)
protein from N. tabacum will be discussed in the light of how differential glycosylation may be used to regulate molecular interactions within the
ECM. 相似文献
19.
Andrey V. Kulikov Alexander S. Vdovin Boris Zhivotovsky Vladimir Gogvadze 《Cellular and molecular life sciences : CMLS》2014,71(12):2325-2333
Rapidly proliferating tumor cells easily become hypoxic. This results in acquired stability towards treatment with anticancer drugs. Here, we show that cells grown at 0.1 % oxygen are more resistant towards treatment with the conventionally used anticancer drugs doxorubicin and cisplatin. The stimulation of apoptosis, as assessed by the number of cells in the SubG1 fraction of the cell cycle, release of cytochrome c into the cytosol, activation of caspase-3, and cleavage of PARP, was markedly suppressed under low oxygen content or when hypoxia was mimicked by deferoxamine. Hypoxia or deferoxamine treatment was accompanied by stabilization of the hypoxia-inducible factor (HIF-1). The downregulation of HIF-1 using siRNA technique restored cell sensitivity to treatment under hypoxic conditions to the levels detected under normoxic conditions. In contrast to cisplatin or doxorubicin, α-tocopheryl succinate (α-TOS), a compound that targets mitochondria, stimulated cell death irrespective of the oxygen concentration. Moreover, under hypoxic condition cell death induced by α-TOS was even enhanced. Thus, α-TOS can successfully overcome resistance to treatment caused by hypoxia, which makes α-TOS an attractive candidate for antitumor therapy via mitochondrial targeting. 相似文献
20.
Berton A Selvais C Lemoine P Henriet P Courtoy PJ Marbaix E Emonard H 《Cellular and molecular life sciences : CMLS》2007,64(5):610-620
Matrix metalloproteinase-7 (MMP-7, matrilysin- 1) modulates crucial biological events by processing many epithelial cell surface-associated
effectors. We addressed MMP-7 interaction with human epithelial cells and its resulting activity. In human endometrium, a
model of controlled tissue remodeling, proMMP-7 was diffusely immunolocalized inside epithelial cells, whereas MMP-7 delineated
their entire plasma membrane. Endometrial explants preferentially retained active MMP-7, but not proMMP-7. Endometrial epithelial
cells and carcinoma cells from various tissues bound active MMP-7. Endometrial carcinoma-derived Ishikawa cells showed high
affinity (KD
of ~2.5 nM) and capacity (~260 000 sites per cell) for MMP-7. MMP-7 binding decreased by extracting membrane sterols or interfering
with heparan sulfate proteoglycans, and was abrogated by tissue inhibitors of metalloproteinase-2 (TIMP-2) or synthetic MMP
inhibitors. Bound MMP-7 not only remained fully active towards a macromolecular substrate but also became resistant to TIMP-2.
We conclude that MMP-7-selective targeting to the plasma membrane of epithelial cells promotes its activity by conferring
resistance to TIMP-2.
A. Berton, C. Selvais: These authors contributed equally to this work.
P. J. Courtoy, E. Marbaix, H. Emonard: These authors contributed equally to the supervision of this work.
Received 20 September 2006; received after revision 30 November 2006; accepted 18 January 2007 相似文献