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1.
The role of thrombospondin-1 in apoptosis 总被引:3,自引:0,他引:3
The thrombospondins are a family of extracellular proteins that participate in cell-to-cell and cell-to-matrix communication.
They regulate cellular phenotype during tissue genesis and repair. Five family members, each representing a separate gene
product, probably exist in most vertebrate species. Like most extracellular proteins, the thrombospondins are composed of
several structural domains that are responsible for the numerous biological functions that have been described for this protein
family. Considerable progress has been made towards understanding the function of thrombospondins. The role of thrombospondin
in the process of apoptosis or programmed cell death has recently come into focus. In this review we will concentrate on the
role of thrombospondin-1 in the broad field of apoptotis research.
Received 5 December 2001; received after revision 28 March 2002; accepted 28 March 2002 相似文献
2.
From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance 总被引:31,自引:0,他引:31
Litman T Druley TE Stein WD Bates SE 《Cellular and molecular life sciences : CMLS》2001,58(7):931-959
The ATP binding cassette (ABC) superfamily of membrane transporters is one of the largest protein classes known, and counts numerous proteins involved in the trafficking of biological molecules across cell membranes. The first known human ABC transporter was P-glycoprotein (P-gp), which confers multidrug resistance (MDR) to anticancer drugs. In recent years, we have obtained an increased understanding of the mechanism of action of P-gp as its ATPase activity, substrate specificity and pharmacokinetic interactions have been investigated. This review focuses on the functional characterization of P-gp, as well as other ABC transporters involved in MDR: the family of multidrug-resistance-associated proteins (MRP1-7), and the recently discovered ABC half-transporter MXR (also known as BCRP, ABCP and ABCG2). We describe recent progress in the analysis of protein structure-function relationships, and consider the conceptual problem of defining and identifying substrates and inhibitors of MDR. An in-depth discussion follows of how coupling of nucleotide hydrolysis to substrate transport takes place, and we propose a scheme for the mechanism of P-gp function. Finally, the clinical correlations, both for reversal of MDR in cancer and for drug delivery, are discussed. 相似文献
3.
Edward J. Andress Michael Nicolaou Farrell McGeoghan Kenneth J. Linton 《Cellular and molecular life sciences : CMLS》2017,74(13):2513-2524
Bile salts are natural detergents required to solubilise dietary fat and lipid soluble vitamins. They are synthesised in hepatocytes and secreted into the luminal space of the biliary tree by the bile salt export pump (BSEP), an ATP-binding cassette (ABC) transporter in the canalicular membrane. BSEP deficiency causes cytotoxic accumulation of bile salts in the hepatocyte that results in mild-to-severe forms of cholestasis. The resulting inflammation can also progress to hepatocellular cancer via a novel mechanism involving upregulation of proliferative signalling pathways. A second ABC transporter of the canalicular membrane is also critical for bile formation. ABCB4 flops phosphatidylcholine into the outer leaflet of the membrane to be extracted by bile salts in the canalicular space. These mixed micelles reduce the detergent action of the bile salts and protect the biliary tree from their cytotoxic activity. ABCB4 deficiency also causes cholestasis, and might be expected to cause cholangitis and predispose to liver cancer. Non-synonymous SNPs in ABCB4 have now been described in patients with liver cancer or with inflammatory liver diseases that are known to predispose to cancer, but data showing that the SNPs are sufficiently deleterious to be an etiological factor are lacking. Here, we report the first characterisation at the protein level of six ABCB4 variants (D243A, K435T, G535D, I490T, R545C, and S978P) previously found in patients with inflammatory liver diseases or liver cancer. All significantly impair the transporter with a range of phenotypes exhibited, including low abundance, intracellular retention, and reduced floppase activity, suggesting that ABCB4 deficiency is the root cause of the pathology in these cases. 相似文献
4.
Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters 总被引:9,自引:0,他引:9
Di Pietro A Conseil G Pérez-Victoria JM Dayan G Baubichon-Cortay H Trompier D Steinfels E Jault JM de Wet H Maitrejean M Comte G Boumendjel A Mariotte AM Dumontet C McIntosh DB Goffeau A Castanys S Gamarro F Barron D 《Cellular and molecular life sciences : CMLS》2002,59(2):307-322
Cancer cell resistance to chemotherapy is often mediated by overexpression of P-glycoprotein, a plasma membrane ABC (ATP-binding cassette) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. P-glycoprotein (ABCB1, according to the human gene nomenclature committee) consists of two homologous halves each containing a transmembrane domain (TMD) involved in drug binding and efflux, and a cytosolic nucleotide-binding domain (NBD) involved in ATP binding and hydrolysis, with an overall (TMD-NBD)2 domain topology. Homologous ABC multidrug transporters, from the same ABCB family, are found in many species such as Plasmodiumfalciparum and Leishmania spp. protozoa, where they induce resistance to antiparasitic drugs. In yeasts, some ABC transporters involved in resistance to fungicides, such as Saccharomyces cerevisiae Pdr5p and Snq2p, display a different (NBD-TMD)2 domain topology and are classified in another family, ABCG. Much effort has been spent to modulate multidrug resistance in the different species by using specific inhibitors, but generally with little success due to additional cellular targets and/or extrusion of the potential inhibitors. This review shows that due to similarities in function and maybe in three-dimensional organization of the different transporters, common potential modulators have been found. An in vitro 'rational screening' was performed among the large flavonoid family using a four-step procedure: (i) direct binding to purified recombinant cytosolic NBD and/or full-length transporter, (ii) inhibition of ATP hydrolysis and energy-dependent drug interaction with transporter-enriched membranes, (iii) inhibition of cell transporter activity monitored by flow cytometry and (iv) chemosensitization of cell growth. The results indicate that prenylated flavonoids bind with high affinity, and strongly inhibit drug interaction and nucleotide hydrolysis. As such, they constitute promising potential modulators of multidrug resistance. 相似文献
5.
Callebaut I Eudes R Mornon JP Lehn P 《Cellular and molecular life sciences : CMLS》2004,61(2):230-242
The cystic fibrosis transmembrane conductance regulator (CFTR) protein is encoded by the gene that is defective in cystic fibrosis, the most common lethal inherited disease among the Caucasian population. CFTR belongs to the ABC transporter superfamily, whose members form macromolecular architectures composed of two membrane-spanning domains and two nucleotide-binding domains (NBDs). The experimental structures of NBDs from several ABC transporters have recently been solved, opening new avenues for understanding the structure/function relationships and the consequences of some disease-causing mutations of CFTR. Based on a detailed sequence/structure analysis, we propose here a three-dimensional model of the human CFTR NBD heterodimer. This model, which is in agreement with recent experimental data, highlights the specific features of the CFTR asymmetric active sites located at the interface between the two NBDs. Moreover, additional CFTR-specific features can be identified at the subunit interface, which may play critical roles in active site interdependence and are uncommon in other NBD dimers.Received 16 October 2003; received after revision 16 November 2003; accepted 21 November 2003 相似文献
6.
Isabelle Callebaut Brice Hoffmann Pierre Lehn Jean-Paul Mornon 《Cellular and molecular life sciences : CMLS》2017,74(1):3-22
The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a member of the ATP-binding cassette (ABC) transporter superfamily that functions as an ATP-gated channel. Considerable progress has been made over the last years in the understanding of the molecular basis of the CFTR functions, as well as dysfunctions causing the common genetic disease cystic fibrosis (CF). This review provides a global overview of the theoretical studies that have been performed so far, especially molecular modelling and molecular dynamics (MD) simulations. A special emphasis is placed on the CFTR-specific evolution of an ABC transporter framework towards a channel function, as well as on the understanding of the effects of disease-causing mutations and their specific modulation. This in silico work should help structure-based drug discovery and design, with a view to develop CFTR-specific pharmacotherapeutic approaches for the treatment of CF in the context of precision medicine. 相似文献
7.
Genes involved in breast cancer metastasis to bone 总被引:12,自引:0,他引:12
Metastasis to bone occurs frequently in advanced breast cancer and is accompanied by debilitating skeletal complications.
Current treatments are palliative and new therapies that specifically prevent the spread of breast cancer to bone are urgently
required. While our understanding of interactions between breast cancer cells and bone cells has greatly improved, we still
know little about the molecular determinants that regulate specific homing of breast cancer cells to the bone. In this review,
we focus on genes that have been implicated in migration and adhesion of breast cancer cells to bone, as well as genes that
promote tumor cell proliferation in the bone microenvironment. In addition, the review discusses new technologies, including
better animal models, that will further assist with the identification of the molecular determinants of bone metastasis and
will guide the development of new therapies.
Received 25 January 2002; received after revision 27 March 2002; accepted 5 April 2002
RID="*"
ID="*"Corresponding author. 相似文献
8.
Mornon JP Prat K Dupuis F Boisset N Callebaut I 《Cellular and molecular life sciences : CMLS》2002,59(12):2144-2154
Prion diseases are neurodegenerative disorders associated with a conformational conversion of the prion PrP protein, in which
the β-strand content increases and that of the α helix decreases. However, the structure of the pathogenous form PrPSc, occurring after conformational conversion of the normal cellular form PrPC, is not yet known. From sequence analysis, we have previously proposed that helix H2 of the prion PrPC structure might be a key region for this structural conversion. More recently, we identified the TATA box-binding protein
fold as a putative scaffold that may locally satisfy the predicted secondary-structure organisation of PrPSc. In the present analysis, we detail the schematic construction of PrPSc monomeric and dimeric models, based on this hypothesis. These models are globally compatible with available data and therefore
may provide further insights into the structurally and functionally elusive PrP protein.
Some comments are also devoted to a comparison of the yeast Ure2p prion and animal prions.
Received 29 July 2002; received after revision 24 October 2002; accepted 24 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
9.
A dynamic view of peptides and proteins in membranes 总被引:1,自引:0,他引:1
Bechinger B 《Cellular and molecular life sciences : CMLS》2008,65(19):3028-3039
Biological membranes are highly dynamic supramolecular arrangements of lipids and proteins, which fulfill key cellular functions.
Relatively few high-resolution membrane protein structures are known to date, although during recent years the structural
databases have expanded at an accelerated pace. In some instances the structures of reaction intermediates provide a stroboscopic
view on the conformational changes involved in protein function. Other biophysical approaches add dynamic aspects and allow
one to investigate the interactions with the lipid bilayers. Membrane-active peptides fulfill many important functions in
nature as they act as antimicrobials, channels, transporters or hormones, and their studies have much increased our understanding
of polypeptide-membrane interactions. Interestingly several proteins have been identified that interact with the membrane
as loose arrays of domains. Such conformations easily escape classical high-resolution structural analysis and the lessons
learned from peptides may therefore be instructive for our understanding of the functioning of such membrane proteins.
Received 11 March 2008; received after revision 2 May 2008; accepted 5 May 2008 相似文献
10.
Di Francesco AM Ruggiero A Riccardi R 《Cellular and molecular life sciences : CMLS》2002,59(11):1914-1927
Oxaliplatin (Eloxatine) is a third-generation platinum compound which has shown a wide antitumour effect both in vitro and
in vivo, a better safety profile than cisplatin and a lack of cross-resistance with cisplatin and carboplatin. In this scenario,
oxaliplatin may represent an innovative and challenging drug extending the antitumour activity in diseases such as gastrointestinal
cancer that are not usually sensitive to these coordination complexes. Oxaliplatin has a non-hydrolysable diaminocyclohexane
(DACH) carrier ligand which is maintained in the final cytotoxic metabolites of the drug. Like cisplatin, oxaliplatin targets
DNA producing mainly 1,2-GG intrastrand cross-links. The cellular and molecular aspects of the mechanism of action of oxaliplatin
have not yet been fully elucidated. However, the intrinsic chemical and steric characteristics of the DACH-platinum adducts
appear to contribute to the lack of cross-resistance with cisplatin. To date, mismatch repair and replicative bypass appear
to be the processes most likely involved in differentiating the molecular responses to these agents.
Received 15 March 2002; received after revision 13 May 2002; accepted 21 May 2002
RID="*"
ID="*"Corresponding author. 相似文献
11.
Viviani VR 《Cellular and molecular life sciences : CMLS》2002,59(11):1833-1850
Luciferases are the enzymes that catalyze the reactions that produce light in bioluminescence. Whereas the oxidative mechanism
which leads to light emission is similar for most luciferases, these enzymes and their substrates are evolutionarily unrelated.
Among all bioluminescent groups, insects constitute one of the most diverse in terms of biochemistry. In the fungus-gnats
(Mycetophilidae: Diptera), for example, bioluminescence is generated by two biochemically distinct systems. Despite the diversity,
investigations on insect luciferases and biochemistry have been conducted mostly with fireflies. The luciferases from the
related phengodid beetles, which can produce green to red bioluminescence using the same chemistry as firefly luciferases,
have been recently investigated. Beetle luciferases originated from ancestral acyl-CoA ligases. Present data suggest that
conserved motifs among this class of ligases are involved in substrate adenylation. The three-dimensional structure of firefly
luciferase was recently solved and mutagenesis studies have been performed identifying putative residues involved in luciferin
binding and bioluminescence color determination in several beetle luciferases. The knowledge gained through these studies
is helping in the development of useful reporter gene tools for biotechnological and biomedical purposes.
Received 4 March 2002; received after revision 13 May 2002; accepted 21 May 2002 相似文献
12.
Glass R Loesch A Bodin P Burnstock G 《Cellular and molecular life sciences : CMLS》2002,59(5):870-881
We investigated the expression of P2X4 and P2X6 receptors on human umbilical vein endothelial cells (HUVECs) and found that both P2X receptor subtypes on plasma membranes
are largely restricted to areas of cell-cell contact. Co-labelling experiments at the confocal and electron microscopy levels
revealed that P2X4 and P2X6 receptors are strongly co-localised with the cell adhesion molecule VE-cadherin. The P2X4 and P2X6 receptors on plasma membranes at cellular junctions are rapidly (within 5 min) internalised specifically after decreasing
extracellular [Ca2+]. Disruption of microfilaments, microtubules and integrin-mediated adhesion or stimulation of P2 receptors with ATP did not
alter P2X4 and P2X6 receptor expression on HUVEC plasma membranes. Membraneous P2X4 and P2X6 receptors resisted extraction with Triton-X 100, whereas cytoplasmic P2X receptors were Triton-X 100 soluble. P2X4 receptors, but not P2X6 receptors, could be co-immunoprecipitated with VE-cadherin and vice versa. We conclude that P2X4 and P2X6 receptors are associated with VE-cadherin at HUVEC adherens junctions.
Received 15 March 2002; revised 15 March 2002; accepted 19 March 2002 相似文献
13.
Thyroid hormone controls carnitine status through modifications of γ-butyrobetaine hydroxylase activity and gene expression 总被引:1,自引:0,他引:1
Galland S Georges B Le Borgne F Conductier G Dias JV Demarquoy J 《Cellular and molecular life sciences : CMLS》2002,59(3):540-545
The carnitine system plays a key role in β-oxidation of long-chain fatty acids by permitting their transport into the mitochondrial
matrix. The effects of hypothyroidism and hyperthyroidism were studied on γ-butyrobetaine hydroxylase (BBH), the enzyme responsible
for carnitine biosynthesis in the rat. In rat liver, BBH activity was decreased in the hypothyroid state and increased in
hyperthyroid animals. The modifications in BBH activity correlated with changes in the enzyme Vmax values. These changes were
shown to be related to hepatic BBH mRNA abundance. Thyroid hormones are known to interact with lipid metabolism, in particular
by increasing long-chain fatty acid oxidation through activation of carnitine-dependent fatty acid import into mitochondria.
Our study showed that thyroid hormones also increased carnitine bioavailability.
Received 23 October 2001; received after revision 11 January 2002; accepted 15 January 2002 相似文献
14.
Nitrate and nitrite transport in bacteria 总被引:7,自引:0,他引:7
The topological arrangements of nitrate and nitrite reductases in bacteria necessitate the synthesis of transporter proteins
that carry the nitrogen oxyanions across the cytoplasmic membrane. For assimilation of nitrate (and nitrite) there are two
types of uptake system known: ABC transporters that are driven by ATP hydrolysis, and secondary transporters reliant on a
proton motive force. Proteins homologous to the latter type of transporter are also involved in nitrate and nitrite transport
in dissimilatory processes such as denitrification. These proteins belong to the NarK family, which is a branch of the Major
Facilitator Superfamily. The mechanism and substrate specificity of transport via these proteins is unknown, but is discussed
in the light of sequence analysis of members of the NarK family. A hypothesis for nitrate and nitrite transport is proposed
based on the finding that there are two distinct types of NarK. 相似文献
15.
Corda D Hidalgo Carcedo C Bonazzi M Luini A Spanò S 《Cellular and molecular life sciences : CMLS》2002,59(11):1819-1832
Membrane fission is essential in various intracellular dissociative transport steps. The molecular mechanisms by which endocytic
vesicles detach from the plasma membrane are being rapidly elucidated. Much less is known about the fission mechanisms operating
at Golgi tubular networks; these include the Golgi transport and sorting stations, the trans-Golgi and cis-Golgi networks,
where the geometry and physical properties of the membranes differ from those at the cell surface. Here we discuss the lipid
and protein machineries that have so far been related to the fission process, with emphasis on those acting in the Golgi complex.
Received 10 May 2002; received after revision 20 June 2002; accepted 26 June 2002
RID="*"
ID="*"Corresponding author. 相似文献
16.
Ning Zhang Lin-Lin Yao Xiang-dong Li 《Cellular and molecular life sciences : CMLS》2018,75(2):261-273
Class V myosin (myosin-5) is a molecular motor that functions as an organelle transporter. The activation of myosin-5′s motor function has long been known to be associated with a transition from the folded conformation in the off-state to the extended conformation in the on-state, but only recently have we begun to understand the underlying mechanism. The globular tail domain (GTD) of myosin-5 has been identified as the inhibitory domain and has recently been shown to function as a dimer in regulating the motor function. The folded off-state of myosin-5 is stabilized by multiple intramolecular interactions, including head–GTD interactions, GTD–GTD interactions, and interactions between the GTD and the C-terminus of the first coiled-coil segment. Any cellular factor that affects these intramolecular interactions and thus the stability of the folded conformation of myosin-5 would be expected to regulate myosin-5 motor function. Both the adaptor proteins of myosin-5 and Ca2+ are potential regulators of myosin-5 motor function, because they can destabilize its folded conformation. A combination of these regulators provides a versatile scheme in regulating myosin-5 motor function in the cell. 相似文献
17.
A population of ventral neural tube cells has recently been shown to migrate out of the hind brain neural tube via the vagus
nerve and contribute to the developing gastrointestinal tract. Since liver is also innervated by the vagus nerve, we sought
to determine if these cells also migrate into the liver. Ventral neural tube cells in the caudal hindbrain of chick embryos
were tagged with a replication-deficient retroviral vector containing the LacZ gene on embryonic day 2. Embryos were processed
for detection of labeled cells on embryonic day 5 and 11. Labeled cells were seen in the liver on both days and identified
as hepatocytes. Previously, it was believed that all hepatocytes develop from the gut endoderm. Results of the present study
show an additional source for the formation of liver cells.
Received 25 August 1998; received after revision 5 November 1998; accepted 5 November 1998 相似文献
18.
Polyamine-dependent gene expression 总被引:15,自引:0,他引:15
The polyamines spermidine and spermine along with the diamine putrescine are involved in
many cellular processes, including chromatin condensation, maintenance of DNA structure, RNA
processing, translation and protein activation. The polyamines influence the
formation of compacted chromatin and have a well-established role in DNA aggregation. Polyamines
are used in the posttranslational modification of eukaryotic initiation factor 5A, which regulates
the transport and processing of specific RNA. The polyamines also participate in a
novel RNA-decoding mechanism, a translational frameshift, of at least two known genes, the TY1
transposon and mammalian antizyme. Polyamines are crucial for their own regulation and are involved
in feedback mechanisms affecting both polyamine synthesis and catabolism. Recently, it has become
apparent that the polyamines are able to influence the action of the protein kinase
casein kinase 2. Here we address several roles of polyamines in gene expression.Received 27 November 2002; received after revision 9 January 2003; accepted 31 January 2003 相似文献
19.
Izaurralde E 《Cellular and molecular life sciences : CMLS》2001,58(8):1105-1112
The distinguishing feature of eukaryotic cells is the segregation of RNA biogenesis and DNA replication in the nucleus, separate
from the cytoplasmic machinery for protein synthesis. As a consequence, messenger RNAs (mRNAs) and all cytoplasmic RNAs from
nuclear origin need to be transported from their site of synthesis in the nucleus to their final cytoplasmic destination.
Nuclear export occurs through nuclear pore complexes (NPCs) and is mediated by saturable transport receptors, which shuttle
between the nucleus and cytoplasm. The past years have seen great progress in the characterization of the mRNA export pathway
and the identification of proteins involved in this process. A novel family of nuclear export receptors (the NXF family),
distinct from the well-characterized family of importin β-like proteins, has been implicated in the export of mRNA to the cytoplasm.
Received 23 January 2001; received after revision 12 April 2001; accepted 12 April 2001 相似文献
20.
Opposite actions of testosterone and progesterone on UCP1 mRNA expression in cultured brown adipocytes 总被引:3,自引:0,他引:3
Rodriguez AM Monjo M Roca P Palou A 《Cellular and molecular life sciences : CMLS》2002,59(10):1714-1723
The brown adipose tissue (BAT) thermogenic response to diet-induced obesity and cold has been found to be gender dependent.
In the present work, we aimed to investigate the effects of the main physiological male and female sex hormones, i.e. testosterone,
progesterone and 17-β-estradiol, on the expression of uncoupling protein 1 (UCP1) – the main mediator of BAT thermogenesis
– and on UCP2 and lipid accumulation in rodent brown adipocytes differentiated in culture. Testosterone-treated cells showed
fewer and smaller lipid droplets than control cells and a dose-dependent inhibition of UCP1 mRNA expression, under adrenergic
stimulation by norepinephrine (NE). These effects were reverted by the androgen receptor antagonist flutamide, suggesting
they are dependent, at least in part, on the androgen receptor. Progesterone- and 17-β-estradiol-treated cells showed more
and larger lipid droplets and progesterone stimulated NE-induced UCP1 mRNA expression at the lower concentration tested, but
not at higher concentrations, suggesting that for brown adipocytes, this hormone is dose dependent. 17-β-Estradiol did not
have any remarkable effect either on UCP1 or UCP2 mRNA expression. Interestingly, the specific progesterone receptor antagonist
RU486 induced UCP1 and UCP2 mRNAs, including UCP1 mRNA expression in non-NE-treated brown adipocytes, suggesting a profound
effect of this anti-progestagen on brown adipocyte thermogenic capacity. Thus, are conclude that testosterone, 17-β-estradiol,
progesterone and RU486 have distinct actions on brown adipocytes, thus modulating UCP1 and UCP2 mRNA expression and/or lipid
accumulation, and that sex hormones are factors that may explain in part the gender-dependent BAT thermogenic response.
Received 24 June 2002; received after revision 20 August 2002; accepted 26 August 2002
RID="*"
ID="*"Corresponding author. 相似文献