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1.
Opposite pattern of MDR1 and caveolin-1 gene expression in human atherosclerotic lesions and proliferating human smooth muscle cells 总被引:2,自引:0,他引:2
Batetta B Mulas MF Petruzzo P Putzolu M Bonatesta RR Sanna F Cappai A Brotzu G Dessì S 《Cellular and molecular life sciences : CMLS》2001,58(8):1113-1120
Cholesterol esterification and smooth muscle cell (SMC) proliferation are the crucial events in the development of atherosclerotic
lesions. The objective of this study was to analyse cholesterol esterification and the expression of MDR1 (multidrug resistance),
ACAT (acyl-CoA:cholesterol acyltransferase) and caveolin-1 genes in atherosclerotic and healthy vascular walls, in SMCs obtained
from atherosclerotic lesions and saphenous veins. Results demonstrated higher levels of cholesterol esters, ACAT and MDR1
mRNAs and lower levels of caveolin-1 mRNA in atherosclerotic segments compared to adjacent serial sections of the same artery
and the corresponding non-atherosclerotic arteries from cadaveric donors. SMCs isolated from atherosclerotic plaques manifested
an increased capacity to esterify cholesterol and to grow at a faster rate than SMCs isolated from saphenous veins. In addition,
when SMCs from atherosclerotic plaques were cultured in the presence of progesterone, a potent inhibitor of cholesterol esterification,
significant growth suppression was observed. An increase in ACAT and MDR1 expression and a concomitant decrease in caveolin-1
expression were also observed in SMCs isolated from atherosclerotic arteries as early as 12 h after serum stimulation. An
opposite pattern was found when SMCs were treated with progesterone. These findings support the idea that cholesterol esterification
plays a role both in early atherogenesis and in clinical progression of advanced lesions and raise the possibility that the
cholesterol ester pathway might directly modulate the proliferation of SMCs.
Received 5 February 2001; received after revision 15 May 2001; accepted 15 May 2001 相似文献
2.
Ras proteins in the control of the cell cycle and cell differentiation 总被引:12,自引:0,他引:12
The Ras family of small GTPases includes three closely related proteins: H-, K-, and N-Ras. Ras proteins are involved in
the transduction of signals elicited by activated surface receptors, acting as key components by relaying signals downstream
through diverse pathways. Mutant, constitutively activated forms of Ras proteins are frequently found in cancer. While constitutive
Ras activation induces oncogenic-like transformation in immortalized fibroblasts, it causes growth arrest in primary vertebrate
cells. Induction of p53 and cyclin-dependent kinase inhibitors such as p15INK4b, p16INK4a, p19ARF, and p21WAF1 accounts for this response. Interestingly, while ras has usually been regarded as a transforming oncogene, the analysis of Ras function in most of the cellular systems studied
so far indicates that the promotion of differentiation is the most prominent effect of Ras. While in some cell types, particularly
muscle, Ras inhibits differentiation, in others such as neuronal, adipocytic, or myeloid cells, Ras induces differentiation,
in some cases accompanied by growth arrest. Several possible mechanisms for the pleiotropic effects of Ras in animal cells
are discussed.
Received 8 March 2000; received after revision 24 May 2000; accepted 24 May 2000 相似文献
3.
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
4.
Q.-Q. Li X.-X. Cao J.-D. Xu Q. Chen W.-J. Wang F. Tang Z.-Q. Chen X.-P. Liu Z.-D. Xu 《Cellular and molecular life sciences : CMLS》2009,66(3):504-515
We previously reported that treatment with P-glycoprotein (P-gp) substrates promotes in vitro invasion in multidrug-resistant (MDR) breast cancer cells. This effect is initiated by the P-gp pump function and mediated
by interaction of P-gp with some unknown component(s). However, the underlying mechanism(s) remains poorly understood. Here
we confirm a novel physical interaction between P-gp and cellular prion protein (PrPc). Blocking P-gp activity or depletion of PrPc inhibited paclitaxel (P-gp substrate)- induced invasion. Paclitaxel further facilitated the formation of P-gp/PrPc clusters residing in caveolar domains and promoted the association of P-gp with caveolin-1. Both caveolin-1 and the integrity
of caveolae were required for the drug-induced invasion. In addition, the P-gp/PrPc complex also played an important role in anti-apoptotic activity of MCF7/Adr cells.These data provide new insights into the
mode by which MDR breast cancers evade cytotoxic attacks from P-gp substrates and also suggest a role for P-gp/ PrPc interaction in this process.
Received 4 September 2008; received after revision 16 November 2008; accepted 18 November 2008 相似文献
5.
A. T. C. Tsin 《Cellular and molecular life sciences : CMLS》1986,42(8):952-954
Summary The membrane fraction of the retinal pigment epithelium (RPE) of the frog (Rana pipiens) catalyzed the esterification of tritiated retinol to retinyl esters. This esterification reaction was inhibited in the presence of 3,4-didehydroretinol. 相似文献
6.
7.
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
8.
Apaf1 has been described as the core of the apoptosome. Deficiency in murine Apaf1 leads to embryonic lethality with a phenotype affecting many aspects of developmental apoptosis. In the developing brain,
Apaf1 is a death regulator of the neuronal founder cells. Combined intercrosses of mouse lines mutant for members of the mitochondrial
death pathway are providing us with some clues about the relative regulation existing among neuronal cell populations. Apaf1-deficient embryos display an interesting phenotype in the inner ear and in limb development, which involves different caspase-dependent
and -independent pathways. Moreover, APAF1 is mutated in human melanomas, and its depletion contributes to malignant transformation in a mouse model of cancer. This
review has a double aim: the analysis of the alternatives taken by the embryo to bring into the suicidal program different
cells at different stages, and the relevance of APAF1 in the onset and progression of cancer.
Received 5 March 2001; received after revision 19 April 2001; accepted 4 May 2001 相似文献
9.
Nucleotides are of crucial importance as carriers of energy in all organisms. However, the concept that in addition to their
intracellular roles, nucleotides act as extracellular ligands specifically on receptors of the plasma membrane took longer
to be accepted. Purinergic signaling exerted by purines and pyrimidines, principally ATP and adenosine, occurs throughout
embryologic development in a wide variety of organisms, including amphibians, birds, and mammals. Cellular signaling, mediated
by ATP, is present in development at very early stages, e.g., gastrulation of Xenopus and germ layer definition of chick embryo cells. Purinergic receptor expression and functions have been studied in the development
of many organs, including the heart, eye, skeletal muscle and the nervous system. In vitro studies with stem cells revealed
that purinergic receptors are involved in the processes of proliferation, differentiation, and phenotype determination of
differentiated cells. Thus, nucleotides are able to induce various intracellular signaling pathways via crosstalk with other
bioactive molecules acting on growth factor and neurotransmitter receptors. Since normal development is disturbed by dysfunction
of purinergic signaling in animal models, further studies are needed to elucidate the functions of purinoceptor subtypes in
developmental processes. 相似文献
10.
In higher vertebrates, sulfatases belong to a conserved family of enzymes that are involved in the regulation of cell metabolism
and in developmental cell signaling. They cleave the sulfate from sulfate esters contained in hormones, proteins, and complex
macromolecules. A highly conserved cysteine in their active site is post-translationally converted into formylglycine by the
formylglycine-generating enzyme encoded by SUMF1 (sulfatase modifying factor 1). This post-translational modification activates all sulfatases. Sulfatases are extensively
glycosylated proteins and some of them follow trafficking pathways through cells, being secreted and taken up by distant cells.
Many proteoglycans, glycoproteins, and glycolipids contain sulfated carbohydrates, which are sulfatase substrates. Indeed,
sulfatases operate as decoding factors for a large amount of biological information contained in the structures of the sulfated
sugar chains that are covalently linked to proteins and lipids. Modifications to these sulfate groups have pivotal roles in
modulating specific signaling pathways and cell metabolism in mammals. 相似文献
11.
12.
A population of uterine natural killer (NK) cells, commonly called granulated metrial gland (GMG) cells, differentiates in the mouse uterus during normal pregnancy. Little is known regarding the process of differentiation of GMG cells or of other NK cell subsets. It has been suggested that macrophage precursors, under the combined influences of the cytokine growth factors colony stimulating factor-1 (CSF-1) and interleukin-2, become NK-cell like in morphology, pattern of target cell lysis and surface antigen phenotype. Mice expressing the mutation osteopetrosis (op/op) are unable to produce the cytokine CSF-1. To determine whether CSF-1 is required for the successful differentiation of uterine NK cells, implantation sites in pregnant,op/op mice were studied histologically. GMG cell differentiation appeared to progress normally inop/op mice studied between days 7 and 14 of gestation. Thus, the growth factor CSF-1 is not required for differentiation of the uterine NK cell subset known as GMG cells and probably GMG cells do not differentiate from macrophage precursor cells which are deficient inop/op mice. 相似文献
13.
Labile protein-methyl ester: Comparison between chemically and enzymatically synthesized 总被引:3,自引:0,他引:3
Summary The rate of hydrolysis of protein-methyl ester, the enzymatic product of S-adenosylmethionine: proteincarboxyl methyltransferase (EC.2.1.1.24) acting on oxidized ribonuclease, was measured at pH 7.1 and 8.6 at 37°C. The half-life of the hydrolysis of the ester is 25 min at pH 7.1, and 4 min at 8.6. The rate of hydrolysis of the enzymatically formed esters at pH 7.0, in 0.1M phosphate buffer, was about 25 times faster than that of esters formed chemically by reaction with methanol in HCl. The lability of the enzymatically synthesized protein-methyl ester suggests that the esterification is specific to sites such that ionization of neighboring amino acid side chains enhances the rate of the hydrolysis.Acknowledgments. This work was supported by Research Grants AM 09603 from the National Institute of Arthritis and Metabolic Diseases, CA 10439 and CA 12226 from the National Cancer Institute, 1-P01-HD-05874 from the National Institute of Child Health and Human Development, National Institutes of Health, GM 20594-03 from National Institute of General Medical Sciences, USA. 相似文献
14.
15.
C. Demetzos P. Magiatis M. A. Typas K. Dimas R. Sotiriadou S. Perez D. Kokkinopoulos 《Cellular and molecular life sciences : CMLS》1997,53(7):587-592
Incubation of kaempferol-3-O-β-D-(6"-E-p-coumaroyl)-glucopyranoside (tiliroside) (1) with Aspergillus nidulans gives the 7-methyl ether of tiliroside (2) which is a new compound. Its structure is determined by spectroscopic methods. Cytotoxic studies of 2 and of its acetylated derivative 2a were carried out in vitro against fourteen human leukemic cell lines. Results clearly show that compound 2 is ineffective against all leukemic cell lines tested. On the contrary, compound 2a exhibited cytotoxic activity against four of the cell lines (HL60, DAUDI, HUT78 and MOLT3) and additionally, a dose- and
time-dependent effect on DNA synthesis.
Received 18 February 1997; received after revision 8 April 1997; accepted 6 May 1997 相似文献
16.
Porcelli AM Ghelli A Mastrocola T Rugolo M 《Cellular and molecular life sciences : CMLS》1999,56(1-2):167-173
The Ca2+ ionophore ionomycin induced cytosolic [Ca2+]i elevation as well as strong activation of Cl− efflux in mouse mammary epithelial cell lines expressing wild-type or mutated (deletion of phenylalaline 508) cystic fibrosis
transmembrane conductance regulator (CFTR) or vector. Ionomycin-induced Cl− efflux was abolished by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, whereas both activators and inhibitors of phospholipase A2 had no effect, indicating the involvement of Ca2+-dependent Cl- channels. Stimulation of arachidonic acid release by ionomycin and phorbol ester was not significantly different between
wild-type or mutated cell lines, whereas vector-transfected cells exhibited a significant higher release, which was shown
to be due to larger amount of immunoreactive cytosolic phospholipase A2. These results indicate that phospholipase A2 activity of C127 cells was not influenced by the presence of wild-type or mutated CFTR.
Received 27 April 1999; received after revision 11 June 1999; accepted 23 July 1999 相似文献
17.
J. Auwerx 《Cellular and molecular life sciences : CMLS》1991,47(1):22-31
Summary THP-1 is a human monocytic leukemia cell line. After treatment with phorbol esters, THP-1 cells differentiate into macrophage-like cells which mimic native monocyte-derived macrophages in several respects. Compared to other human myeloid cell lines, such as HL-60, U937, KG-1, or HEL cell lines, differentiated THP-1 cells behave more like native monocyte-derived macrophages. Because of these characteristics, the THP-1 cell line provides a valuable model for studying the mechanisms involved in macrophage differentiation, and for exploring the regulation of macrophage-specific genes as they relate to physiological functions displayed by these cells. 相似文献
18.
The human leukemia cell line, THP-1: a multifacetted model for the study of monocyte-macrophage differentiation 总被引:8,自引:0,他引:8
J Auwerx 《Experientia》1991,47(1):22-31
THP-1 is a human monocytic leukemia cell line. After treatment with phorbol esters, THP-1 cells differentiate into macrophage-like cells which mimic native monocyte-derived macrophages in several respects. Compared to other human myeloid cell lines, such as HL-60, U937, KG-1, or HEL cell lines, differentiated THP-1 cells behave more like native monocyte-derived macrophages. Because of these characteristics, the THP-1 cell line provides a valuable model for studying the mechanisms involved in macrophage differentiation, and for exploring the regulation of macrophage-specific genes as they relate to physiological functions displayed by these cells. 相似文献
19.
Dictyostelium discoideum cells shed vesicles with associated DNA and vital stain Hoechst 33342 总被引:2,自引:0,他引:2
I. Tatischeff M. Bomsel C. de Paillerets H. Durand B. Geny D. Segretain E. Turpin A. Alfsen 《Cellular and molecular life sciences : CMLS》1998,54(5):476-487
Dictyostelium discoideum cells are highly resis tant to xenobiotics. We previously observed that these primitive eukaryotic cells contain a 170-kDa
P-glycoprotein, mediating multidrug resistance in mammalian cells, but nonfunctional in Dictyostelium cells. We show here that D. discoideum cells vitally stained with the DNA-specific dye, Hoechst 33342, release fluorescent material in their culture medium. Electron
microscopy and lipid analysis demonstrate the vesicular nature of this material. Moreover, nucleic acids associate with these
extracellular vesicles independently of Hoechst vital staining. The main vesicular DNA component exhibits a size >21 kb. Shedding
of microvesicles during cell growth is not concomitant with programmed cell death. We propose that these extracellular vesicles
are involved in a new cellular resistance mechanism against xenobiotics. Furthermore, since the association of DNA with vesicles
occurs in physiological growth conditions and independently of vital staining, the new shedding process might be involved
in a more general intercellular mechanism.
Received 14 November 1997; received after revision 16 March 1998; accepted 16 March 1998 相似文献
20.
Diterpene acids as larval growth inhibitors 总被引:1,自引:0,他引:1
C. A. Elliger D. F. Zinkel B. G. Chan A. C. Waiss Jr. 《Cellular and molecular life sciences : CMLS》1976,32(11):1364-1366
Summary Kaurenoic and trachylobanoic acids from sunflower inhibited larval development in several Lepidoptera species. The tricyclic resin acids were also effective in curtailing growth ofPectinophora gossypiella and either reduction to carbinol or esterification of the carboxyl group lowered activity. Partial reversal of growth inhibition in the presence of relatively large amounts of cholesterol suggests an interaction with the insects' hormonal system.Acknowledgment. We wish to thankM. Rose andJ. Baker for insect bioassays. 相似文献