共查询到20条相似文献,搜索用时 31 毫秒
1.
Yuliia Kaljas Chengqian Liu Maksym Skaldin Chengxiang Wu Qing Zhou Yuanan Lu Ivona Aksentijevich Andrey V. Zavialov 《Cellular and molecular life sciences : CMLS》2017,74(3):555-570
At sites of inflammation and tumor growth, the local concentration of extracellular adenosine rapidly increases and plays a role in controlling the immune responses of nearby cells. Adenosine deaminases ADA1 and ADA2 (ADAs) decrease the level of adenosine by converting it to inosine, which serves as a negative feedback mechanism. Mutations in the genes encoding ADAs lead to impaired immune function, which suggests a crucial role for ADAs in immune system regulation. It is not clear why humans and other mammals possess two enzymes with adenosine deaminase activity. Here, we found that ADA2 binds to neutrophils, monocytes, NK cells and B cells that do not express CD26, a receptor for ADA1. Moreover, the analysis of CD4+ T-cell subset revealed that ADA2 specifically binds to regulatory T cells expressing CD39 and lacking the receptor for ADA1. Also, it was found that ADA1 binds to CD16? monocytes, while CD16+ monocytes preferably bind ADA2. A study of the blood samples from ADA2-deficient patients showed a dramatic reduction in the number of lymphocyte subsets and an increased concentration of TNF-α in plasma. Our results suggest the existence of a new mechanism, where the activation and survival of immune cells is regulated through the activities of ADA2 or ADA1 anchored to the cell surface. 相似文献
2.
Cytochalasin D (CD) has been extensively used for assessing the role of the actin cytoskeleton in different biological processes. However, effects of CD have not always been consistent and CD-treated cells have been found to contain irregular spots of F-actin. By transfecting MCF-7 cells with an actin-enhanced yellow fluorescent protein fusion protein we show that, in vivo, CD induces actin aggregation de novo, while simultaneously depolymerizing preexisting actin cytoskeletal components. We also show that CD-induced actin aggregates bind the F-actin-selective drug phalloidin and associate with proteins involved in cell signaling as well as with receptors and endosomal markers (active MAP kinases, paxillin, erbB2, transferrin, Rab-5), but not with clathrin, protein kinase A, protein tyrosine phosphatase 1B, or tubulin. Thus, CD induces new sites of actin aggregation that selectively associate with several important regulatory proteins. Failure of CD to interupt a biological process may therefore not prove that the process is independent of actin aggregation. 相似文献
3.
Lindsey T. Brinton Hillary S. Sloane Mark Kester Kimberly A. Kelly 《Cellular and molecular life sciences : CMLS》2015,72(4):659-671
Exosomes offer new insight into cancer biology with both diagnostic and therapeutic implications. Because of their cell-to-cell communication, exosomes influence tumor progression, metastasis, and therapeutic efficacy. They can be isolated from blood and other bodily fluids to reveal disease processes occurring within the body, including cancerous growth. In addition to being a reservoir of cancer biomarkers, they can be re-engineered to reinstate tumor immunity. Tumor exosomes interact with various cells of the microenvironment to confer tumor-advantageous changes that are responsible for stromal activation, induction of the angiogenic switch, increased vascular permeability, and immune escape. Exosomes also contribute to metastasis by aiding in the epithelial-to-mesenchymal transition and formation of the pre-metastatic niche. Furthermore, exosomes protect tumor cells from the cytotoxic effects of chemotherapy drugs and transfer chemoresistance properties to nearby cells. Thus, exosomes are essential to many lethal elements of cancer and it is important to understand their biogenesis and role in cancer. 相似文献
4.
Isbert S Wagner K Eggert S Schweitzer A Multhaup G Weggen S Kins S Pietrzik CU 《Cellular and molecular life sciences : CMLS》2012,69(8):1353-1375
The amyloid precursor protein (APP) is part of a larger gene family, which has been found to form homo- or heterotypic complexes
with its homologues, whereby the exact molecular mechanism and origin of dimer formation remains elusive. In order to assess
the cellular location of dimerization, we have generated a cell culture model system in CHO-K1 cells, stably expressing human
APP, harboring dilysine-based organelle sorting motifs [KKAA-endoplasmic reticulum (ER); KKFF-Golgi], accomplishing retention
within early secretory compartments. We show that APP exists as disulfide-bonded dimers upon ER retention after it was isolated
from cells, and analyzed by SDS-polyacrylamide gel electrophoresis under non-reducing conditions. In contrast, strong denaturing
and reducing conditions, or deletion of the E1 domain, resulted in the disappearance of those dimers. Thus we provide first
evidence that a fraction of APP can associate via intermolecular disulfide bonds, likely generated between cysteines located
in the extracellular E1 domain. We particularly visualize APP dimerization itself and identified the ER as subcellular compartment
of its origin using biochemical or split GFP approaches. Interestingly, we also found that minor amounts of SDS-resistant
APP dimers were located to the cell surface, revealing that once generated in the oxidative environment of the ER, dimers
remained stably associated during transport. In addition, we show that APP isoforms encompassing the Kunitz-type protease
inhibitor (KPI) domain exhibit a strongly reduced ability to form cis-directed dimers in the ER, whereas trans-mediated cell aggregation of Drosophila Schneider S2-cells was isoform independent. Thus, suggesting that steric properties of KPI-APP might be the cause for weaker
cis-interaction in the ER, compared to APP695. Finally, we provide evidence that APP/APLP1 heterointeractions are likewise initiated
in the ER. 相似文献
5.
Marta Bolos Carlos Spuch Lara Ordoñez-Gutierrez Francisco Wandosell Isidro Ferrer Eva Carro 《Cellular and molecular life sciences : CMLS》2013,70(15):2787-2797
β-amyloid (Aβ) can promote neurogenesis, both in vitro and in vivo, by inducing neural progenitor cells to differentiate into neurons. The choroid plexus in Alzheimer’s disease (AD) is burdened with amyloid deposits and hosts neuronal progenitor cells. However, neurogenesis in this brain tissue is not firmly established. To investigate this issue further, we examined the effect of Aβ on the neuronal differentiation of choroid plexus epithelial cells in several experimental models of AD. Here we show that Aβ regulates neurogenesis in vitro in cultured choroid plexus epithelial cells as well as in vivo in the choroid plexus of APP/Ps1 mice. Treatment with oligomeric Aβ increased proliferation and differentiation of neuronal progenitor cells in cultured choroid plexus epithelial cells, but decreased survival of newly born neurons. These Aβ-induced neurogenic effects were also observed in choroid plexus of APP/PS1 mice, and detected also in autopsy tissue from AD patients. Analysis of signaling pathways revealed that pre-treating the choroid plexus epithelial cells with specific inhibitors of TyrK or MAPK diminished Aβ-induced neuronal proliferation. Taken together, our results support a role of Aβ in proliferation and differentiation in the choroid plexus epithelial cells in Alzheimer’s disease. 相似文献
6.
Simone Eggert A. C. Gonzalez C. Thomas S. Schilling S. M. Schwarz C. Tischer V. Adam P. Strecker V. Schmidt T. E. Willnow G. Hermey C. U. Pietrzik E. H. Koo Stefan Kins 《Cellular and molecular life sciences : CMLS》2018,75(2):301-322
Proteolytic cleavage of the amyloid precursor protein (APP) by α-, β- and γ-secretases is a determining factor in Alzheimer’s disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic Aβ production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting Aβ production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD. 相似文献
7.
Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease 总被引:1,自引:1,他引:0
Mudò G Mäkelä J Di Liberto V Tselykh TV Olivieri M Piepponen P Eriksson O Mälkiä A Bonomo A Kairisalo M Aguirre JA Korhonen L Belluardo N Lindholm D 《Cellular and molecular life sciences : CMLS》2012,69(7):1153-1165
8.
Del Val M Iborra S Ramos M Lázaro S 《Cellular and molecular life sciences : CMLS》2011,68(9):1543-1552
CD8+ T lymphocytes screen the surface of all cells in the body to detect pathogen infection or oncogenic transformation. They
recognize peptides derived from cellular proteins displayed at the plasma membrane by major histocompatibility complex (MHC)
class I molecules. Peptides are mostly by-products of cytosolic proteolytic enzymes. Peptidic ligands of MHC class I molecules
are also generated in the secretory and vesicular pathways. Features of protein substrates, of proteases and of available
MHC class I molecules for loading peptides in these compartments shape a singular collection of ligands that also contain
different, longer, and lower affinity peptides than ligands produced in the cytosol. Especially in individuals who lack the
transporters associated with antigen processing, TAP, and in infected and tumor cells where TAP is blocked, which thus have
no supply of peptides derived from the cytosol, MHC class I ligands generated in the secretory and vesicular pathways contribute
to shaping the CD8+ T lymphocyte response. 相似文献
9.
Marta Bolos Desireé Antequera Jesús Aldudo Henrike Kristen María Jesús Bullido Eva Carro 《Cellular and molecular life sciences : CMLS》2014,71(15):2947-2955
The choroid plexuses (CP) release numerous biologically active enzymes and neurotrophic factors, and contain a subpopulation of neural progenitor cells providing the capacity to proliferate and differentiate into other types of cells. These characteristics make CP epithelial cells (CPECs) excellent candidates for cell therapy aiming at restoring brain tissue in neurodegenerative illnesses, including Alzheimer’s disease (AD). In the present study, using in vitro approaches, we demonstrated that CP were able to diminish amyloid-β (Aβ) levels in cell cultures, reducing Aβ-induced neurotoxicity. For in vivo studies, CPECs were transplanted into the brain of the APP/PS1 murine model of AD that exhibits advanced Aβ accumulation and memory impairment. Brain examination after cell implantation revealed a significant reduction in brain Aβ deposits, hyperphosphorylation of tau, and astrocytic reactivity. Remarkably, the transplantation of CPECs was accompanied by a total behavioral recovery in APP/PS1 mice, improving spatial and non-spatial memory. These findings reinforce the neuroprotective potential of CPECs and the use of cell therapies as useful tools in AD. 相似文献
10.
Monogenetic determinants of Alzheimer's disease: APP mutations 总被引:2,自引:0,他引:2
A. M. Goate 《Cellular and molecular life sciences : CMLS》1998,54(9):897-901
Mutations within exons 16 and 17 of the β-amyloid precursor protein (APP) gene were the first known cause of familial Alzheimer's disease. These mutations are rare
and have been reported in a handful of families exhibiting autosomal dominant inheritance of Alzheimer's disease with age
of onset around 50 years. In vitro and in vivo studies have demonstrated that each of these mutations alters proteolytic processing
of APP, resulting in an increase in the production of Aβ42, a highly fibrillogenic peptide, that spontaneously aggregates and deposits in the brain. Transgenic mice carrying a mutant
human APP gene also show age-dependent β-amyloid (Aβ) deposition in the brain. The rate of deposition in these mice can be modified by apolipoprotein E expression. 相似文献
11.
Behavior of neural stem cells in the Alzheimer brain 总被引:3,自引:0,他引:3
12.
13.
Current knowledge on exosome biogenesis and release 总被引:1,自引:1,他引:0
Nina Pettersen Hessvik Alicia Llorente 《Cellular and molecular life sciences : CMLS》2018,75(2):193-208
Exosomes are nanosized membrane vesicles released by fusion of an organelle of the endocytic pathway, the multivesicular body, with the plasma membrane. This process was discovered more than 30 years ago, and during these years, exosomes have gone from being considered as cellular waste disposal to mediate a novel mechanism of cell-to-cell communication. The exponential interest in exosomes experienced during recent years is due to their important roles in health and disease and to their potential clinical application in therapy and diagnosis. However, important aspects of the biology of exosomes remain unknown. To explore the use of exosomes in the clinic, it is essential that the basic molecular mechanisms behind the transport and function of these vesicles are better understood. We have here summarized what is presently known about how exosomes are formed and released by cells. Moreover, other cellular processes related to exosome biogenesis and release, such as autophagy and lysosomal exocytosis are presented. Finally, methodological aspects related to exosome release studies are discussed. 相似文献
14.
Ida J. Llewellyn-Smith 《Cellular and molecular life sciences : CMLS》1987,43(7):813-821
Summary The discovery of neuropeptides in enteric neurons has revolutionized the study of the microcircuitry of the enteric nervous system. Form immunohistochemistry, it is now clear that some individual enteric neurons contain several different neuropeptides with or without other transmitter-specific markers and that these markers occur in various combinations. There is evidence from experiments in which nerve pathways are interrupted that populations of enteric neurons with different combinations of markers have different projection patterns, sending their processes to distinct targets using different routes. Correlations between the neurochemistry of enteric neurons and the types of synaptic inputs they receive are also beginning to emerge from electrophysiological studies. These findings imply that enteric neurons are chemically coded by the combinations of peptides and other transmitter-related substances they contain and that the coding of each population correlates with its role in the neuronal pathways that control gastrointestinal function. 相似文献
15.
I J Llewellyn-Smith 《Experientia》1987,43(7):813-821
The discovery of neuropeptides in enteric neurons has revolutionized the study of the microcircuitry of the enteric nervous system. From immunohistochemistry, it is now clear that some individual enteric neurons contain several different neuropeptides with or without other transmitter-specific markers and that these markers occur in various combinations. There is evidence from experiments in which nerve pathways are interrupted that populations of enteric neurons with different combinations of markers have different projection patterns, sending their processes to distinct targets using different routes. Correlations between the neurochemistry of enteric neurons and the types of synaptic inputs they receive are also beginning to emerge from electrophysiological studies. These findings imply that enteric neurons are chemically coded by the combinations of peptides and other transmitter-related substances they contain and that the coding of each population correlates with its role in the neuronal pathways that control gastrointestinal function. 相似文献
16.
The molecular link between β- and γ-secretase activity on the amyloid β precursor protein 总被引:1,自引:1,他引:0
Alzheimer’s disease (AD) is characterized by an accumulation in the brain of amyloid β peptides (Aβ). The production of Aβ
requires two sequential cleavages induced by β- and γ-secretases on the β-amyloid precursor protein (APP). Altered activity
of these secretases is involved in the pathogenesis of AD. The expression and activity of β-secretase (BACE1) is augmented
in the brain in late-onset sporadic AD. Mutant presenilin 1 (PS1), the major genetic defect of early-onset familial AD (FAD),
alters the activity of γ-secretase, leading to increased production of Aβ42. Here we review the role of oxidative stress as
a molecular link between the β- and the γ-secretase activities, and provide a mechanistic explanation of the pathogenesis
of sporadic late-onset AD. We also discuss evidence for a role of the same mechanism in the pathogenesis of familial AD carrying
PS1 mutations. 相似文献
17.
Kristin T. Jacobsen Kerstin Iverfeldt 《Cellular and molecular life sciences : CMLS》2009,66(14):2299-2318
The Alzheimer’s amyloid precursor protein (APP) belongs to a conserved gene family that also includes the mammalian APLP1
and APLP2, the Drosophila APPL, and the C. elegans APL-1. The biological function of APP is still not fully clear. However, it is known that the APP family proteins have redundant
and partly overlapping functions, which demonstrates the importance of studying all APP family members to gain a more complete
picture. When APP was first cloned, it was speculated that it could function as a receptor. This theory has been further substantiated
by studies showing that APP and its homologues bind both extracellular ligands and intracellular adaptor proteins. The APP
family proteins undergo regulated intramembrane proteolysis (RIP), generating secreted and cytoplasmic fragments that have
been ascribed different functions. In this review, we will discuss the APP family with focus on biological functions, binding
partners, and regulated processing. 相似文献
18.
Apolipoprotein E (apoE) ɛ4 allele is a genetic risk factor for late-onset familial and sporadic Alzheimer’s disease (AD).
In the central nervous system, apoE is secreted mainly by astrocytes as a constituent of high-density lipoproteins. A recent
study using apoE knockout mice provided strong evidence that apoE promotes cerebral deposition of amyloid β protein (Aβ).
However, no clear explanation of the pathogenesis of apoE-induced AD has been provided. Here we discuss two possible mechanisms
by which apoE might enhance Aβ deposition. One is the intracellular pathway in which apoE is internalized by neurons and induces
lysosomal accumulation of Aβ and amyloidogenic APP (amyloid precursor protein) fragments, leading to neuronal death. The other
is the extracellular pathway in which apoE-containing lipoproteins are trapped by Aβ1–42 deposits mobilizing soluble Aβ peptides
and consequently enlarge amyloid plaques. These two mechanisms may operate at different stages of AD pathogenesis and suggest
a chaperone-like function for the apoE molecule.
Received 4 February 1999; received after revision 9 April 1999; accepted 23 April 1999 相似文献
19.
Irena Crnković-Mertens Julia Bulkescher Christina Mensger Felix Hoppe-Seyler Karin Hoppe-Seyler 《Cellular and molecular life sciences : CMLS》2010,67(11):1895-1905
Livin (ML-IAP) is a cancer-associated member of the inhibitor of apoptosis protein (IAP) family. By yeast two-hybrid screening
of a randomized peptide expression library, we isolated short linear peptides that specifically bind to Livin, but not to
other IAPs. Intracellular expression of the peptides sensitized livin-expressing cancer cells toward different pro-apoptotic stimuli. The bioactive peptides neither showed sequence homologies
to Smac-derived IAP inhibitors, nor did they interfere with the binding of Livin to Smac. Intracellular expression of the
peptides did not affect the levels or the subcellular distribution of Livin. Growth of livin-expressing tumor cells was inhibited in colony formation assays by the Livin-targeting peptides. These findings provide evidence
that the targeted inhibition of Livin by peptides represents a viable approach for the apoptotic sensitization and growth
inhibition of tumor cells. The inhibitory peptides isolated here could form a novel basis for the development of therapeutically
useful Livin inhibitors. 相似文献
20.
J. Demarquoy 《Cellular and molecular life sciences : CMLS》1993,49(4):345-348
Citrullinemia is a recessive genetic disease caused by a deficiency in argininosuccinate synthetase (AS). Retroviruses were used to transduce the human AS gene into cultured human cells. Using amphotropic viruses with high titer (>106 cfu/ml), we were able to correct the defect in cultured fibroblasts from citrullinemic patients. Retroviral transduction of the human AS gene into human bone marrow cells was also studied. Co-cultivation was used to infect the cells and up to 80% of progenitor cells were found to be carrying and expressing the AS retrovirus after infection. When the infected cells were kept in culture, integration and expression of the retrovirus was observed. Retroviral sequences were present and expressed in the cultured bone marrow-derived cells for up to 10 weeks. 相似文献