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1.
Laura Pellegrini Andrea Wetzel Simone Grannó George Heaton Kirsten Harvey 《Cellular and molecular life sciences : CMLS》2017,74(3):409-434
Cytoskeletal homeostasis is essential for the development, survival and maintenance of an efficient nervous system. Microtubules are highly dynamic polymers important for neuronal growth, morphology, migration and polarity. In cooperation with several classes of binding proteins, microtubules regulate long-distance intracellular cargo trafficking along axons and dendrites. The importance of a delicate interplay between cytoskeletal components is reflected in several human neurodegenerative disorders linked to abnormal microtubule dynamics, including Parkinson’s disease (PD). Mounting evidence now suggests PD pathogenesis might be underlined by early cytoskeletal dysfunction. Advances in genetics have identified PD-associated mutations and variants in genes encoding various proteins affecting microtubule function including the microtubule-associated protein tau. In this review, we highlight the role of microtubules, their major posttranslational modifications and microtubule associated proteins in neuronal function. We then present key evidence on the contribution of microtubule dysfunction to PD. Finally, we discuss how regulation of microtubule dynamics with microtubule-targeting agents and deacetylase inhibitors represents a promising strategy for innovative therapeutic development. 相似文献
2.
Morrison EE 《Cellular and molecular life sciences : CMLS》2007,64(3):307-317
Microtubule dynamic instability is fundamentally important to the way cells respond to their environment and segregate their genetic material. A disparate class of proteins defined by their localisation to growing microtubule plus ends ('+TIPS') play a key role in controlling microtubule dynamics and organisation. They directly impact upon the behaviour of the microtubule tip and link this structure to interfaces that include kinetochores and the cortex of the cell. Surprisingly, some +TIPs also have important functions at the microtubule minus end. These properties contribute to the important roles played by +TIPs in processes such as mitosis and cell migration. This review examines how recent advances have impacted our understanding of +TIP function in mammalian cells, with emphasis on the emergence of the EB1 family as a core component of +TIP activities. An overview of the use of +TIP imaging as a tool for the cell biologist is also presented. 相似文献
3.
Microtubules (MTs), key components of the cytoskeleton, are dynamic polymers of tubulin that form a well-organized network
of polarized tube filaments. MT dynamics are highly regulated both spacially and temporally by several MT-related proteins,
themselves regulated by several kinases and phosphatases via signaling cascades, and also by coordinated interactions with
actin cytoskeleton and adhesion sites. Regulation of MT dynamics is crucial for mitosis, cell migration, cell signaling and
trafficking. MT-targeted drugs (MTDs), which constitute a major anticancer drug family with antimitotic and antiangiogenic
properties, inhibit tumor progression mainly by altering MT dynamics in both cancer and endothelial cells. Identification
of proteins regulating the MT network will lead to a better understanding of tumor progression regulators and will be helpful
in improving cancer therapy.
Received 22 July 2005; received after revision 8 September 2005; accepted 12 September 2005 相似文献
4.
Recombinant expression of perchloric acid-soluble protein reduces cell proliferation 总被引:3,自引:0,他引:3
Kanouchi H Tachibana H Oka T Yamada K 《Cellular and molecular life sciences : CMLS》2001,58(9):1340-1343
Perchloric acid-soluble protein (PSP) may play an important role in the regulation of cellular physiological functions because
it has been highly conserved throughout evolution; however, this role has not been well elucidated. In previous reports, we
suggested that PSP regulates cell proliferation. In this study, we examined the effect of PSP expression on proliferation
of the normal rat kidney cell line NRK-52E, the rat hepatocyte cell line RLN-10, and the rat hepatoma cell line dRLh-84. Cells
transfected with pcDNA-sense-PSP (pcDNA-S-PSP) over-expressed PSP mRNA and protein, and cell proliferation of the transfected
cells was suppressed compared with that of cells transfected with pcDNA-empty (pcDNA-E). Cell viability of pcDNA-S-PSP-transfected
cells was similar to that of pcDNA-E-transfected cells. Thus, over-expression of PSP suppresses cell proliferation without
any influence on cell viability. These findings are the first to report an inhibitory activity of PSP on cell proliferation.
Received 27 April 2001; received after revision 8 June 2001; accepted 8 June 2001 相似文献
5.
Axonal transport of neurofilaments in normal and disease states 总被引:5,自引:0,他引:5
Miller CC Ackerley S Brownlees J Grierson AJ Jacobsen NJ Thornhill P 《Cellular and molecular life sciences : CMLS》2002,59(2):323-330
Neurofilaments are among the most abundant organelles in neurones. They are synthesised in cell bodies and then transported
into and through axons by a process termed 'slow axonal transport' at a rate that is distinct from that driven by conventional
fast motors. Several recent studies have now demonstrated that this slow rate of transport is actually the consequence of
conventional fast rates of movement that are interrupted by extended pausing. At any one time, most neurofilaments are thus
stationary. Accumulations of neurofilaments are a pathological feature of several human neurodegenerative diseases suggesting
that neurofilament transport is disrupted in disease states. Here, we review recent advances in our understanding of neurofilament
transport in both normal and disease states. Increasing evidence suggests that phosphorylation of neurofilaments is a mechanism
for regulating their transport properties, possibly by promoting their detachment from the motor(s). In some neurodegenerative
diseases, signal transduction mechanisms involving neurofilament kinases and phosphatases may be perturbed leading to disruption
of transport.
Received 11 July 2001; received after revision 30 August 2001; accepted 31 August 2001 相似文献
6.
Novel regulation and function of Src tyrosine kinase 总被引:4,自引:0,他引:4
Src tyrosine kinase is a critical signal transducer that modulates a wide variety of cellular functions. Misregulation of
Src leads to cell transformation and cancer. Heterotrimeric guanine-nucleotide-binding proteins (G proteins) are another group
of signaling molecules that transduce signals from cell-surface receptors to generate physiological responses. Recently, it
was discovered that Gαs and Gαi could directly stimulate Src family tyrosine kinase activity. This novel regulation of Src
tyrosine kinase by G proteins provides insights into the adenylyl cyclase-independent signaling mechanisms involved in ligand-induced
receptor desensitization, internalization and other physiological processes.
Received 17 August 2001; received after revision 22 October 2001; accepted 24 October 2001 相似文献
7.
Matthias Samereier Otto Baumann Irene Meyer Ralph Gräf 《Cellular and molecular life sciences : CMLS》2011,68(2):275-287
We have localized TACC to the microtubule-nucleating centrosomal corona and to microtubule plus ends. Using RNAi we proved
that Dictyostelium TACC promotes microtubule growth during interphase and mitosis. For the first time we show in vivo that both TACC and XMAP215
family proteins can be differentially localized to microtubule plus ends during interphase and mitosis and that TACC is mainly
required for recruitment of an XMAP215-family protein to interphase microtubule plus ends but not for recruitment to centrosomes
and kinetochores. Moreover, we have now a marker to study dynamics and behavior of microtubule plus ends in living Dictyostelium cells. In a combination of live cell imaging of microtubule plus ends and fluorescence recovery after photobleaching (FRAP)
experiments of GFP-α-tubulin cells we show that Dictyostelium microtubules are dynamic only in the cell periphery, while they remain stable at the centrosome, which also appears to harbor
a dynamic pool of tubulin dimers. 相似文献
8.
Stamenović D 《Cellular and molecular life sciences : CMLS》2008,65(22):3592-3605
Rheological properties of living cells determine how cells interact with their mechanical microenvironment and influence their
physiological functions. Numerous experimental studies have show that mechanical contractile stress borne by the cytoskeleton
and weak power-law viscoelasticity are governing principles of cell rheology, and that the controlling physics is at the level
of integrative cytoskeletal lattice properties. Based on these observations, two concepts have emerged as leading models of
cytoskeletal mechanics. One is the tensegrity model, which explains the role of the contractile stress in cytoskeletal mechanics,
and the other is the soft glass rheology model, which explains the weak power-law viscoelasticity of cells. While these two
models are conceptually disparate, the phenomena that they describe are often closely associated in living cells for reasons
that are largely unknown. In this review, we discuss current understanding of cell rheology by emphasizing the underlying
biophysical mechanism and critically evaluating the existing rheological models.
Received 25 May 2008; received after revision 19 June 2008; accepted 1 July 2008 相似文献
9.
Lisowska E 《Cellular and molecular life sciences : CMLS》2002,59(3):445-455
Glycosylation of proteins is a common event and contributes to protein antigenic properties. Most data have been obtained
from model studies on glycoprotens with well-defined structure or synthetic glycopeptides and their respective monoclonal
antibodies. Antibodies raised against glycoprotein antigens may be specific for their carbohydrate units which are recognized
irrespective of the protein carrier (carbohydrate epitopes), or in the context of the adjacent amino acid residues (glycopeptidic
epitopes). Conformation or proper exposure of peptidic epitopes of glycoproteins is also frequently modulated by glycosylation
due to intramolecular carbohydrate-protein interactions. The effects of glycosylation are broad: glycosylation may 'inactivate'
the peptidic epitope or may be required for its reactivity with the antibody, depending on the structure of the antigenic
site and antibody fine specificity. Evidence is increasing that similar effects of glycosylation pertain to T cell-dependent
cellular immune responses. Glycosylated peptides can be bound and presented by MHC class I or II molecules and elicit glycopeptide-specific
T cell clones.
Received 5 July 2001; received after revision 9 October 2001; accepted 11 October 2001 相似文献
10.
Anne Nehlig Angie Molina Sylvie Rodrigues-Ferreira Stéphane Honoré Clara Nahmias 《Cellular and molecular life sciences : CMLS》2017,74(13):2381-2393
The regulation of microtubule dynamics is critical to ensure essential cell functions, such as proper segregation of chromosomes during mitosis or cell polarity and migration. End-binding protein 1 (EB1) is a plus-end-tracking protein (+TIP) that accumulates at growing microtubule ends and plays a pivotal role in the regulation of microtubule dynamics. EB1 autonomously binds an extended tubulin-GTP/GDP-Pi structure at growing microtubule ends and acts as a molecular scaffold that recruits a large number of regulatory +TIPs through interaction with CAP-Gly or SxIP motifs. While extensive studies have focused on the structure of EB1-interacting site at microtubule ends and its role as a molecular platform, the mechanisms involved in the negative regulation of EB1 have only started to emerge and remain poorly understood. In this review, we summarize recent studies showing that EB1 association with MT ends is regulated by post-translational modifications and affected by microtubule-targeting agents. We also present recent findings that structural MAPs, that have no tip-tracking activity, physically interact with EB1 to prevent its accumulation at microtubule plus ends. These observations point out a novel concept of “endogenous EB1 antagonists” and emphasize the importance of finely regulating EB1 function at growing microtubule ends. 相似文献
11.
Wong RW 《Cellular and molecular life sciences : CMLS》2003,60(1):113-118
Generation of genetically engineered mice with either gain-of-function or loss-of-function mutations is the most popular
technique for determining gene functions and the interrelationship between molecules in vivo. These models have provided a
wealth of information about the developmental and physiological roles of oncogenes and growth factors. To date, transgenic
techniques have been used extensively to study the functions of the epidermal growth factor (EGF) family. This review highlights
some of the major recent findings pertinent to the EGF receptor (EGFR) and its ligands with special reference to elucidating
how EGF and its related growth factors work together to regulate reproduction, growth and development. Finally, future investigations
on ligand-ligand communications, EGFR and its ligands in neural stem cell research, and the mechanisms of EGFR signaling and
trafficking in cells are also suggested.
Received 24 May 2002; received after revision 15 July 2002; accepted 16 July 2002 相似文献
12.
Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) 总被引:4,自引:0,他引:4
R. Kakkar R. V. S. Raju R. K. Sharma 《Cellular and molecular life sciences : CMLS》1999,55(8-9):1164-1186
13.
André Ferreira da Silva Francesca Romana Mariotti Valdemar Máximo Silvia Campello 《Cellular and molecular life sciences : CMLS》2014,71(12):2313-2324
Mitochondria are highly dynamic and functionally versatile organelles that continuously fragment and fuse in response to different physiological needs of the cell. The list of proteins that strictly regulate the morphology of these organelles is constantly growing, adding new players every day and new pieces to the comprehension and elucidation of this complex machinery. The structural complexity of mitochondria is only paralled by their functional versatility. Indeed, changes in mitochondria shape play critical roles in vertebrate development programmed cell death and in various processes of normal cell physiology, such as calcium signaling, reactive oxygen species production, and lifespan. Here, we present the latest findings on the regulation of mitochondrial dynamics and some of their physiological roles, focusing on cell migration. In cells where migration represents a crucial function in their physiology, such as T and tumoral metastatic cells, mitochondria need to be fragmented and recruited to specific subcellular regions to make movement possible. In depth analysis of this role of mitochondrial dynamics should help in identifying potential targeted therapy against cancer or in improving the immune system’s efficiency. 相似文献
14.
Ma Y Cai S Lu Q Lu X Jiang Q Zhou J Zhang C 《Cellular and molecular life sciences : CMLS》2008,65(19):3100-3109
Inhibition of protein deacetylation arrests cells in mitosis, but the mechanism is unknown. To understand why inhibiting protein
deacetylation causes cell cycle arrest, we treated HeLa cells beyond G1/S transition with trichostatin A (TSA), a potent protein
deacetylase inhibitor, and found that the cells arrested at prometaphase with ectopic spindles and unaligned chromosomes.
The hyper-acetylated cells encountered a serious microtubule (MT)-kinetochore attachment problem, although the kinetochores
are intact at ultrastructural level. By immunofluorescence staining of kinetochore proteins, we found that the pericentromeric
H3K9Me3-HP1 pathway was disrupted and that the CENP-A-dependent outer plate protein dynamics of kinetochores was greatly diminished
by the drug treatment. The treatment also caused the loss of chromosome passenger complex (CPC), the proposed error checking
system, from centromere and impaired the microtubule dynamics of the cells. Overall, we propose that deacetylation inhibition
impairs MT-kinetochore attachment through disrupting the centromere function and altering the kinetochore composition and
MT dynamics.
Received 30 April 2008; received after revision 28 July 2008; accepted 14 August 2008 相似文献
15.
Species-specific cell adhesion in marine sponges is mediated by a new family of modular proteoglycans whose general supramolecular
structure resembles that of hyalectans. However, neither their protein nor their glycan moieties have significant sequence
homology to other proteoglycans, despite having protein subunits equivalent to link proteins and to proteoglycan monomer core
proteins, and glycan subunits equivalent to hyaluronan and to the glycosaminoglycans of hyalectans. In some species, these
molecular components are assembled into a structure with a circular core formed by the link protein- and hyaluronan-like subunits.
Besides their involvement in cell adhesion, these sponge proteoglycans, for which we propose the term spongicans, participate
in signal transduction processes and are suspected to play a role in sponge self-nonself recognition. Their in vivo roles
and the mild methods used to purify large amounts of functionally active spongicans make them ideal models to study the functions
and possible new applications of proteoglycans in biomedical research.
Received 21 May 2002; received after revision 5 July 2002; accepted 10 July 2002
RID="*"
ID="*"Corresponding author. 相似文献
16.
The Ror receptor tyrosine kinase family 总被引:6,自引:0,他引:6
Forrester WC 《Cellular and molecular life sciences : CMLS》2002,59(1):83-96
Receptor tyrosine kinases (RTKs) participate in numerous developmental decisions. Ror RTKs are a family of orphan receptors
that are related to muscle specific kinase (MuSK) and Trk neurotrophin receptors. MuSK assembles acetylcholine receptors at
the neuromuscular junction [1, 2], and Trk receptors function in the developing nervous system (reviewed in [3-5]). Rors have
been identified in nematodes, insects and mammals. Recent studies have begun to shed light on Ror function during development.
In most species, Rors are expressed in many tissue types during development. Analyses of mutants that are defective in the
single nematode Ror demonstrate a role in cell migration and in orienting cell polarity. Mice lacking one of the two Ror gene
products display defects in bone and heart formation. Similarly, two different human bone development disorders, dominant
brachydactyly B and recessive Robinow syndrome, result from mutations in one of the human Ror genes.
Received 17 April 2001; received after revision 2 July 2001; accepted 4 July 2001 相似文献
17.
Hepatitis C virus (HCV), a positive-sense, single-stranded RNA virus of the Flaviviridae family, is a major cause of chronic
hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Its RNA is difficult to study because biological materials
are scarce and RNA replication is of low efficiency. This review focuses on the structure and functions of HCV RNA along with
their biological and clinical significance. Despite the challenging characteristics of HCV, significant progress has been
made in understanding the properties of HCV RNA and developing viral replication systems toward the improvement of antiviral
therapies.
Received 15 January 2001; received after revision 2 March 2001; accepted 18 April 2001 相似文献
18.
The mitochondrial PHB complex: roles in mitochondrial respiratory complex assembly, ageing and degenerative disease 总被引:16,自引:0,他引:16
Nijtmans LG Artal SM Grivell LA Coates PJ 《Cellular and molecular life sciences : CMLS》2002,59(1):143-155
Although originally identified as putative negative regulators of the cell cycle, recent studies have demonstrated that the
PHB proteins act as a chaperone in the assembly of subunits of mitochondrial respiratory chain complexes. The two PHB proteins,
Phb1p and Phb2p, are located in the mitochondrial inner membrane where they form a large complex that represents a novel type
of membrane-bound chaperone. On the basis of its native molecular weight, the PHB-complex should contain 12-14 copies of both
Phb1p and Phb2p. The PHB complex binds directly to newly synthesised mitochondrial translation products and stabilises them
against degradation by membrane-bound metalloproteases belonging to the family of mitochondrial triple-A proteins. Sequence
homology assigns Phb1p and Phb2p to a family of proteins which also contains stomatins, HflKC, flotillins and plant defence
proteins. However, to date only the bacterial HflKC proteins have been shown to possess a direct functional homology with
the PHB complex. Previously assigned actions of the PHB proteins, including roles in tumour suppression, cell cycle regulation,
immunoglobulin M receptor binding and apoptosis seem unlikely in view of any hard evidence in their support. Nevertheless,
because the proteins are probably indirectly involved in ageing and cancer, we assess their possible role in these processes.
Finally, we suggest that the original name for these proteins, the prohibitins, should be amended to reflect their roles as
proteins that hold badly formed subunits, thereby keeping the nomenclature already in use but altering its meaning to reflect
their true function more accurately.
Received 21 May 2001; received after revision 2 July 2001; accepted 24 July 2001 相似文献
19.
Molecular basis of autosomal-dominant polycystic kidney disease 总被引:5,自引:0,他引:5
Gallagher AR Hidaka S Gretz N Witzgall R 《Cellular and molecular life sciences : CMLS》2002,59(4):682-693
Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic diseases in humans. The discovery
that mutations in the PKD1 and PKD2 genes are responsible for ADPKD has sparked extensive research efforts into the physiological and pathogenetic role of polycystin-1
and polycystin-2, the proteins encoded by these two genes. While polycystin-1 may mediate the contact among cells or between
cells and the extracellular matrix, a lot of evidence suggests that polycystin-2 represents an endoplasmic reticulum-bound
cation channel. Cyst development has been compared to the growth of benign tumors and this view is highlighted by the model
that a somatic mutation in addition to the germline mutation is responsible for cystogenesis (two-hit model of cyst formation).
Since in vitro polycystin-1 and polycystin-2 interact through their COOH termini, the two proteins possibly act in a common
pathway, which controls the width of renal tubules. The loss of one protein may lead to a disruption of this pathway and to
the uncontrolled expansion of tubules. Our increasing knowledge of the molecular events in ADPKD has also started to be useful
in designing novel diagnostic and therapeutic strategies.
Received 12 September 2001; received after revision 7 November 2001; accepted 7 November 2001 相似文献
20.
Sara Proietti Alessandra Cucina Russel J. Reiter Mariano Bizzarri 《Cellular and molecular life sciences : CMLS》2013,70(12):2139-2157
Melatonin is involved in many physiological functions and it plays an important role in many pathological processes as well. Melatonin has been shown to reduce the incidence of experimentally induced cancers and can significantly inhibit the growth of some human tumors, namely hormone-dependent cancers. The anticancer effects of melatonin have been observed in breast cancer, both in in vivo with models of chemically induced rat mammary tumors, and in vitro studies on human breast cancer cell lines. Melatonin acts at different physiological levels and its antitumoral properties are supported by a set of complex, different mechanisms of action, involving apoptosis activation, inhibition of proliferation, and cell differentiation. 相似文献