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1.
Protein-O-mannosyltransferases (Pmt proteins) catalyse the addition of mannose to serine or threonine residues of secretory proteins.
This modification was described first for yeast and later for other fungi, mammals, insects and recently also for bacteria.
O-mannosylation depends on specific isoforms of the three Pmt1, 2 and 4 subfamilies. In fungi, O-mannosylation determines the structure and integrity of cell walls, as well as cellular differentiation and virulence. O-mannosylation of specific secretory proteins of the human fungal pathogen Candida albicans and of the bacterial pathogen Mycobacterium tuberculosis contributes significantly to virulence. In mammals and insects, Pmt proteins are essential for cellular differentiation and
development, while lack of Pmt activity causes Walker-Warburg syndrome (muscular dystrophy) in humans. The susceptibility
of human cells to certain viruses may also depend on O-mannosyl chains. This review focuses on the various roles of Pmt proteins in cellular differentiation, development and virulence.
Received 6 September 2007; received after revision 3 October 2007; accepted 5 October 2007 相似文献
2.
Suzuki Y 《Cellular and molecular life sciences : CMLS》2008,65(3):351-353
We have proposed a chemical chaperone therapy for lysosomal diseases, based on a paradoxical phenomenon that an exogenous
competitive inhibitor of low molecular weight stabilizes the target mutant molecule and restores its catalytic activity as
a molecular chaperone intracellularly. After Fabry disease experiments, we investigated a new synthetic chaperone compound
N-octyl-4-epi-β-valienamine (NOEV) in a GM1-gangliosidosis model mice. Orally administered NOEV entered the brain through the blood-brain barrier, enhanced β-galactosidase
activity, reduced the substrate storage, and clinically improved neurological deterioration. We hope that chemical chaperone
therapy will prove useful for some patients with GM1-gangliosidosis and potentially other lysosomal storage diseases with central nervous system involvement.
Received 10 October 2007; received after revision 31 October 2007; accepted 6 November 2007 相似文献
3.
Cheema U Brown RA Alp B MacRobert AJ 《Cellular and molecular life sciences : CMLS》2008,65(1):177-186
Tissue hypoxia results in rapid angiogenesis in vivo, triggered by angiogenic proteins, including vascular endothelial growth factor (VEGF). Current views of tissue viability
are founded on whether ‘deeper-lying’ cells receive sufficient nutrients and oxygen for normal activity and ultimately survival.
For intact tissues, levels of such essential nutrients are governed by micro-vascular perfusion. However, there have been
few effective quantitatively defined 3D models, which enable testing of the interplay or interdependence of matrix and cell
density, and path diffusion on oxygen consumption in vitro. As a result, concepts on cell vulnerability to low oxygen levels, together with the nature of cellular responses are ill
defined. The present study has adapted a novel, optical fibre-based system for in situ, real-time oxygen monitoring within three-dimensionally-spiralled cellular collagen constructs, which were then unfurled
to enable quantitative, spatial measurements of VEGF production in different parts of the same construct exposed to different
oxygen levels. A VEGF response was elicited by cells exposed to low oxygen levels (20 mmHg), primarily within the construct
core.
Received 3 August 2007; received after revision 24 October 2007; accepted 29 October 2007
An erratum to this article is available at . 相似文献
4.
Yasuda O Takemura Y Kawamoto H Rakugi H 《Cellular and molecular life sciences : CMLS》2008,65(3):354-358
Aspirin exerts anti-thrombotic action by acetylating and inactivating cyclooxygenase-1, preventing the production of thromboxane
A
2 in platelets. Through this inhibition of platelet function, aspirin is considered as a preventative of ischemic diseases
such as coronary and cerebral infarction. However, many studies have revealed that aspirin has other beneficial actions in
addition to its anti-platelet activity. For example, aspirin may confer some benefit against colorectal cancer. Here, we discuss
the involvement of inflammation in atherosclerosis and how aspirin exerts its beneficial actions in atherosclerotic diseases
and cancer.
Received 30 September 2007; received after revision 31 October 2007; accepted 6 November 2007 相似文献
5.
Strell C Lang K Niggemann B Zaenker KS Entschladen F 《Cellular and molecular life sciences : CMLS》2007,64(24):3306-3316
The extravasation of leukocytes and tumor cells is a multi-step process with the involvement of various adhesion molecules
depending on the three steps rolling, adhesion, and diapedesis. We have developed an in vitro model, by which we investigated the rolling and adhesion of neutrophil granulocytes and MDA-MB-468 human breast carcinoma
cells to lung endothelial cells under physiological flow-conditions. We found that norepinephrine had an inhibitory function
on the fMLP-promoted adhesion of neutrophil granulocytes due to a down-regulation of β2-integrin. Furthermore, neutrophil
granulocytes serve as linking cells for the interaction of the MDA-MB-468 cells with the endothelium, which are both β2-integrin
negative, but express the β2-integrin ligand ICAM-1. In addition, we show here that N-cadherin is up-regulated on the endothelial
cells and on neutrophil granulocytes in response to fMLP. This up-regulation resulted in a significant increase of adherent
MDA-MB-468 cells, which are also N-cadherin positive.
Received 3 September 2007; received after revision 17 October 2007; accepted 22 October 2007 相似文献
6.
Salminen A Ojala J Huuskonen J Kauppinen A Suuronen T Kaarniranta K 《Cellular and molecular life sciences : CMLS》2008,65(7-8):1049-1058
Research on aging in model organisms has revealed different molecular mechanisms involved in the regulation of the lifespan.
Studies on Saccharomyces cerevisiae have highlighted the role of the Sir2 family of genes, human Sirtuin homologs, as the longevity factors. In Caenorhabditis elegans, the daf-16 gene, a mammalian homolog of FoxO genes, was shown to function as a longevity gene. A wide array of studies has
provided evidence for a role of the activation of innate immunity during aging process in mammals. This process has been called
inflamm-aging. The master regulator of innate immunity is the NF-κB system. In this review, we focus on the several interactions
of aging-associated signaling cascades regulated either by Sirtuins and FoxOs or NF-κB signaling pathways. We provide evidence
that signaling via the longevity factors of FoxOs and SIRT1 can inhibit NF-κB signaling and simultaneously protect against inflamm-aging process.
Received 4 October 2007; received after revision 7 November 2007; accepted 9 November 2007 相似文献
7.
Courtois G 《Cellular and molecular life sciences : CMLS》2008,65(7-8):1123-1132
CYLD is a protein with tumor suppressor properties which was originally discovered associated with cylindromatosis, an inherited
cancer exclusively affecting the folicullo-sebaceous-apocrine unit of the epidermis. CYLD exhibits deubiquitinating activity
and acts as a negative regulator of NF-κB and JNK signaling through its interaction with NEMO and TRAF2. Recent data suggest
that this is unlikely to be its unique function in vivo. CYLD has also been shown to control other seemingly disparate cellular processes, such as proximal T cell receptor signaling,
TrkA endocytosis and mitosis. In each case, this enzyme appears to act by regulating a specific type of polyubiquitination,
K63 polyubiquitination, that does not result in recognition and degradation of proteins by the proteasome but instead controls
their activity through diverse mechanisms.
Received 6 October 2007; received after revision 2 November 2007; accepted 23 November 2007 相似文献
8.
Hellgren M Kaiser C de Haij S Norberg A Höög JO 《Cellular and molecular life sciences : CMLS》2007,64(23):3129-3138
Subunit interaction in sorbitol dehydrogenase (SDH) has been studied with in vitro and in silico methods identifying a vital hydrogen-bonding network, which is strictly conserved among mammalian SDH proteins. Mutation
of one of the residues in the hydrogen-bonding network, Tyr110Phe, abolished the enzymatic activity and destabilized the protein
into tetramers, dimers and monomers as judged from gel filtration experiments at different temperatures compared to only tetramers
for the wild-type protein below 307 K. The determined equilibrium constants revealed a large difference in Gibbs energy (8
kJ/mol) for the tetramer stability between wild-type SDH and the mutated form Tyr110Phe SDH. The results focus on a network
of coupled hydrogen bonds in wild-type SDH that uphold the protein interface, which is specific and favorable to electrostatic,
van der Waals and hydrogen-bond interactions between subunits, interactions that are crucial for the catalytic power of SDH.
Received 13 July 2007; received after revision 30 September 2007; accepted 1 October 2007 相似文献
9.
Rosenstiel P Jacobs G Till A Schreiber S 《Cellular and molecular life sciences : CMLS》2008,65(9):1361-1377
NOD-like receptors (NLRs) comprise a family of cytosolic proteins that have been implicated as ancient cellular sentinels
mediating protective immune responses elicited by intracellular pathogens or endogenous danger signals. Genetic variants in
NLR genes have been associated with complex chronic inflammatory barrier diseases (e.g. Crohn disease, bronchial asthma). In
this review, we focus on the molecular pathophysiology of NLRs in the context of chronic inflammatory diseases and pinpoint
recent advances in the evolutionary understanding of NLR biology. We propose that the field of NLRs may serve as a prototype
for how a comprehensive understanding of an element of the immunological barrier will eventually lead to the development of
targeted diagnostic, therapeutic and/or preventive strategies.
Received 29 October 2007; received after revision 10 December 2007; accepted 19 December 2007 相似文献
10.
Investigations into mechanisms that restrict the recovery of functions after an injury to the brain or the spinal cord have
led to the discovery of specific neurite growth inhibitory factors in the adult central nervous system (CNS) of mammals. Blocking
their growth-suppressive function resulted in disinhibition of axonal growth, i.e. growth of cultured neurons on inhibitory
CNS tissue in vitro and regeneration of injured axons in vivo. The enhanced regenerative and compensatory fibre growth was often accompanied by a substantial improvement in the functional
recovery after CNS injury. The first clinical studies to assess the therapeutic potential of compounds that neutralize growth
inhibitors or interfere with their downstream signalling are currently in progress. This review discusses recent advances
in the understanding of how the ‘founder molecule’ Nogo-A and other glialderived growth inhibitors restrict the regeneration
and repair of disrupted neuronal circuits, thus limiting the functional recovery after CNS injuries.
Received 5 April 2007; received after revision 28 September 2007; accepted 1 October 2007 相似文献
11.
MurNAc etherases cleave the uniqued-lactyl ether bond of the bacterial cell wall sugar N-acetylmuramic acid (MurNAc). Members of this newly discovered family of enzymes are widely distributed among bacteria and
are required to utilize peptidoglycan fragments obtained either from the environment or from the endogenous cell wall (i.e.,
recycling). MurNAc etherases are strictly dependent on the substrate MurNAc possessing a free reducing end and a phosphoryl
group at C6. They carry a single conserved sugar phosphate isomerase/sugar phosphate- binding (SIS) domain to which MurNAc
6-phosphate is bound. Two subunits form an enzymatically active homodimer that structurally resembles the isomerase module
of the double-SIS domain protein GlmS, the glucosamine 6-phosphate synthase. Structural comparison provides insights into
the two-step lyase-type reaction mechanism of MurNAc etherases: β-elimination of the D-lactic acid substituent proceeds through
a 2,3-unsaturated sugar intermediate to which water is subsequently added.
Received 31 August 2007; received after revision 12 October 2007; accepted 1 November 2007 相似文献
12.
Specific protein-protein interactions are essential for cellular functions. Experimentally determined three-dimensional structures
of protein-protein complexes offer the possibility to characterize binding interfaces in terms of size, shape and packing
density. Comparison with crystal-packing interfaces representing nonspecific protein-protein contacts gives insight into how
specific binding differs from nonspecific low-affinity binding. An overview is given on empirical structural rules for specific
protein-protein recognition derived from known complex structures. Although single parameters such as interface size, shape
or surface complementary show clear trends for different interface types, each parameter alone is insufficient to fully distinguish
between specific versus crystal-packing contacts. A combination of interface parameters is, however, well suited to characterize a specific interface.
This knowledge provides us with the essential ingredients that make up a specific protein recognition site. It is also of
great value for the prediction of protein binding sites and for the evaluation of predicted complex structures.
Received 1 October 2007; received after revision 9 November 2007; accepted 9 November 2007 相似文献
13.
Menkes disease is caused by mutations in the copper-transporting P1B-type ATPase ATP7A. ATP7A has a dual function: it serves to incorporate copper into copper-dependent enzymes, and it maintains
intracellular copper levels by removing excess copper from the cytosol. To accomplish both functions, the protein traffics
between different cellular locations depending on copper levels.The mechanism for sensing the concentration of copper, for
trafficking, as well as the details of the mechanism of copper translocation across the membrane are unknown.
Received 24 September 2007; received after revision 12 October 2007; accepted 17 October 2007 相似文献
14.
Endoplasmic reticulum stress responses 总被引:7,自引:0,他引:7
Schröder M 《Cellular and molecular life sciences : CMLS》2008,65(6):862-894
In homeostasis, cellular processes are in a dynamic equilibrium. Perturbation of homeostasis causes stress. In this review
I summarize how perturbation of three major functions of the endoplasmic reticulum (ER) in eukaryotic cells–protein folding,
lipid and sterol biosynthesis, and storing intracellular Ca2+ – causes ER stress and activates signaling pathways collectively termed the unfolded protein response (UPR). I discuss how
the UPR reestablishes homeostasis, and summarize our current understanding of how the transition from protective to apoptotic
UPR signaling is controlled, and how the UPR induces inflammatory signaling.
Received 21 August 2007; received after revision 26 October 2007; accepted 29 October 2007 相似文献
15.
γ-Secretase is a promiscuous protease that cleaves bitopic membrane proteins within the lipid bilayer. Elucidating both the
mechanistic basis of γ-secretase proteolysis and the precise factors regulating substrate identification is important because
modulation of this biochemical degradative process can have important consequences in a physiological and pathophysiological
context. Here, we briefly review such information for all major classes of intramembranously cleaving proteases (I-CLiPs),
with an emphasis on γ-secretase, an I-CLiP closely linked to the etiology of Alzheimer’s disease. A large body of emerging
data allows us to survey the substrates of γ-secretase to ascertain the conformational features that predispose a peptide
to cleavage by this enigmatic protease. Because substrate specificity in vivo is closely linked to the relative subcellular compartmentalization of γ-secretase and its substrates, we also survey the
voluminous body of literature concerning the traffic of γ-secretase and its most prominent substrate, the amyloid precursor
protein.
Received 4 October 2007; received after revision 1 December 2007; accepted 7 December 2007 相似文献
16.
The RecQ family of DNA helicases is highly conserved throughout evolution and plays an important role in the maintenance of
genomic stability in all organisms. Mutations in three of the five known family members in humans, BLM, WRN and RECQL4, give rise to disorders that are characterized by predisposition to cancer and premature aging, emphasizing the importance
of studying the RecQ proteins and their cellular activities. Interestingly, three autosomal recessive disorders have been
associated with mutations in the RECQL4 gene: Rothmund-Thomson, RAPADILINO, and Baller-Gerold syndromes, thus making RECQL4 unique within the RecQ family of DNA
helicases. To date, however, the molecular function of RECQL4 and the possible cellular pathways in which it is involved remain
poorly understood. Here, we present an overview of recent findings in connection with RECQL4 and try to highlight different
directions the field could head, helping to clarify the role of RECQL4 in preventing tumorigenesis and maintenance of genome
integrity in humans.
Received 31 October 2006; received after revision 4 January 2007; accepted 5 February 2007 相似文献
17.
Komen JC Distelmaier F Koopman WJ Wanders RJ Smeitink J Willems PH 《Cellular and molecular life sciences : CMLS》2007,64(24):3271-3281
Refsum disease is a rare, inherited neurodegenerative disorder characterized by accumulation of the dietary branched-chain
fatty acid phytanic acid in plasma and tissues caused by a defect in the alphaoxidation pathway. The accumulation of phytanic
acid is believed to be the main pathophysiological cause of the disease. However, the exact mechanism(s) by which phytanic
acid exerts its toxicity have not been resolved. In this study, the effect of phytanic acid on mitochondrial respiration was
investigated. The results show that in digitonin-permeabilized fibroblasts, phytanic acid decreases ATP synthesis, whereas
substrate oxidation per se is not affected. Importantly, studies in intact fibroblasts revealed that phytanic acid decreases both the mitochondrial
membrane potential and NAD(P)H autofluorescence. Taken together, the results described here show that unesterified phytanic
acid exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts.
Received 4 August 2007; received after revision 26 September 2007; accepted 10 October 2007
J. C. Komen, F. Distelmaier: These authors contributed equally to this work. 相似文献
18.
Martínez-Salgado C Rodríguez-Peña AB López-Novoa JM 《Cellular and molecular life sciences : CMLS》2008,65(3):477-492
The mechanisms involved in the development of renal fibrosis are poorly understood. Small Ras GTPases control cell proliferation,
differentiation, cellular growth and apoptosis, with cell-specific expression in the kidney. Cytokines, high glucose medium
or advanced glycation end-products activate Ras in different renal cells. Increased Ras activation has been found in experimental
tubulointerstitial fibrosis. Transforming growth factor-β1 (TGF-β1) and Ras signalling pathways are close related: TGF-β1
overcomes Ras mitogenic effects, and Ras counteracts TGF-β signalling. However, Ras activation is also an intracellular signal
transduction point for several molecules (e.g. TGF-β1) involved in kidney damage. Ras isoforms play different roles in regulating extracellular matrix synthesis in fibroblasts
and mesangial cells. These data give evidence for a role for Ras in renal fibrosis, but no reviews are available on the role
of p21 Ras in this process. Thus, our goal is to review the role of Ras activation and signalling in renal fibrosis.
Received 7 June 2007; received after revision 17 September 2007; accepted 1 October 2007 相似文献
19.
Neuroactive steroids: State of the art and new perspectives 总被引:1,自引:0,他引:1
Melcangi RC Garcia-Segura LM Mensah-Nyagan AG 《Cellular and molecular life sciences : CMLS》2008,65(5):777-797
Neuroactive steroids include synthetic steroidal compounds and endogenous steroids, produced by endocrine glands (hormonal
steroids) or the nervous tissue (neurosteroids), which regulate neural functions. These steroids bind to nuclear receptors
or act through the activation of membrane-associated signaling pathways to modulate various important processes including
the development of the nervous system, neural plasticity and the adaptive responses of neurons and glial cells under pathological
conditions. Reviewed and updated in the present paper are the pleiotropic and protective abilities of neuroactive steroids.
The fundamental evidence and knowledge gained constitute a profound background that offers interesting possibilities for developing
effective strategies against several disorders of the nervous system.
Received 3 September 2007; received after revision 24 October 2007; accepted 29 October 2007 相似文献
20.
Kaiser M Wetzel S Kumar K Waldmann H 《Cellular and molecular life sciences : CMLS》2008,65(7-8):1186-1201
Biologically active small molecules represent the basis for chemical biology applications in which small molecules are used
as chemical tools to probe biological processes. In this report, we review two approaches to design and synthesize compound
libraries for biological screenings, i.e., diversity-oriented synthesis (DOS) and biology-oriented synthesis (BIOS).
Received 23 October 2007; received after revision 26 November 2007; accepted 28 November 2007 相似文献